- Open Access
Mechanisms of lipid malabsorption in Cystic Fibrosis: the impact of essential fatty acids deficiency
Nutrition & Metabolism volume 2, Article number: 11 (2005)
Transport mechanisms, whereby alimentary lipids are digested and packaged into small emulsion particles that enter intestinal cells to be translocated to the plasma in the form of chylomicrons, are impaired in cystic fibrosis. The purpose of this paper is to focus on defects that are related to intraluminal and intracellular events in this life-limiting genetic disorder. Specific evidence is presented to highlight the relationship between fat malabsorption and essential fatty acid deficiency commonly found in patients with cystic fibrosis that are often related to the genotype. Given the interdependency of pulmonary disease, pancreatic insufficiency and nutritional status, greater attention should be paid to the optimal correction of fat malabsorption and essential fatty acid deficiency in order to improve the quality of life and extend the life span of patients with cystic fibrosis.
Cystic fibrosis (CF) is the most common autosomal recessive genetic disease observed in the Caucasian population, affecting about 1 in 2,500 newborns. It is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene discovered in 1989. The gene was cloned from chromosome 7q21-31, is composed of 27 exons and encodes a protein that functions as a chloride channel [1–4]. CFTR has 1,480 amino acids and the molecular weight varies from 140 kDA to 170 kDA, depending upon the degree of posttranslational glycation in the Golgi complex, which appears to vary somewhat according to cell type and genotype. Defective cAMP-dependent chloride ion conductance leads to an imbalance in fluid flow across epithelia, thickened mucus and blocked exocrine ducts in the affected tissues. In addition to respiratory-tract manifestations that represent the major cause of death in CF, the vast majority of young CF subjects have a wide variability of clinical expression, including gastrointestinal, metabolic and nutritional problems [5, 6]. Advances in medical management have led to a continual improvement of life expectancy for CF patients. However, intestinal fat malabsorption remains a persistent feature, given the difficulty of achieving complete correction in clinical practice despite the remarkable benefits resulting from exogenous pancreatic enzyme replacement therapy. [7–11]. The purpose of this article is to present a systematic critical review of literature and data sources pertaining to fat malabsorption in CF, emphasizing the role of abnormal, intraluminal and intracellular factors. Furthermore, the relationship between essential fatty acid deficiency (EFAD) and intestinal fat transport is particularly underscored given its implication in gastrointestinal pathophysiology. To facilitate the reader's appreciation of major gastroenterological problems in CF, we first describe the normal digestive and absorptive processes before addressing the issue of various defective mechanisms in CF.
II Lipids and Essential Fatty Acids (EFAs)
Dietary fat intake represents 35% (100 to 150 g per day) of total calories consumed in the North American diet . Dietary fats are composed mainly of triacylglycerol (TG) with 92–96% long-chain fatty acids . In addition to dietary intake, lipids are derived from bile and desquamated mucosal cells.
Lipids have varied as well as essential functions in organisms. TGs are the principal reserve supply of energy, while phospholipids (PLs) and cholesterol are crucial for the elaboration of cell membranes, and play a functional role in steroid hormone and biliary acid (BA) synthesis. Linoleic (18:2n-6) and linolenic (18:3n-3) acids have recognized functions in growth, the development of the central nervous system, immune and vascular functions, eicosanoid production, membrane fluidity and the control of lipid homeostasis. Adequate EFA levels depend entirely on adequate dietary intake and absorption because mammalian cells cannot synthesize de novo EFA efficiently. Once these EFAs are appropriately absorbed, they can be converted into long-chain polyunsaturated fatty acids (PUFAs) such as arachidonic acid (AA, 20:4n-6), eicosapentaenoic (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3). Conditions leading to fat malabsorption, as in CF, have been associated with a high incidence of EFAD. However, diet-induced EFAD impairs dietary lipid absorption through various mechanisms, which will be thoroughly discussed sin this review.
II.1. CF Patients and EFAD
A high EFAD incidence (85%) has been frequently reported in CF patients [14–19]. EFAD is most marked at infancy  and EFA impairment has been observed most significantly in the cholesteryl ester (CE) fraction [15, 21]. The most often reported abnormalities in plasma are a decrease in linoleic acid and AA, its major metabolites, as well as DHA . This EFA diminution is associated with an elevation in eicosatrienoic acid (20:3n-9), oleic acid (18:1n-9) and palmitoleic acid (16:1n-7) [14, 23, 24], resulting in a rise in the triene/tetraene ratio. It has been suggested that the (20:3n-9/20:4n-6) ratio is a very sensitive and reliable index of EFAD. A value of the ratio above 0.2 indicates an appropriate cutoff for the diagnosis of EFAD . However, results obtained from CF studies vary, possibly as a consequence of different nutritional status, the degree of malabsorption and the severity of the CFTR mutation.
Abnormal EFA status in CF patients does not seem to be the consequence of intestinal malabsorption only, since reduced EFA values are found as early as in the first weeks of life in infants with CF  and they are also present in well-nourished young CF patients who do not receive a low-fat diet and do not present with fat malabsorption [17, 24, 26–28] even with regular pancreatic enzyme therapy . Among other mechanisms related to EFAD, one can mention the excessive oxidation of EFA as an energy source , the exaggerated utilization of eicosanoids as precursors of inflammatory response [30, 31], the higher rate of lipid turnover in cell membranes , the impaired metabolism of EFA with a defect in plasma membrane incorporation, the decreased activity of desaturases [14, 33] and lipid peroxidation .
II.2. Relationship between CFTR and EFAD
CFTR primarily functions as a chloride channel in the apical membrane of the respiratory and gastro-intestinal tracts. An elevation of cAMP within the cell results in increased chloride transport through the CFTR. Movement of water is linked osmotically to such ion transport and chloride secretion represents one likely means of hydrating the mucosal surface of these organs. Other important studies have implicated the CFTR in additional functions, including the regulation of distinct Cl- channel proteins, the modulation of intracellular vesicle and Golgi acidification, and the control of vesicle trafficking [35–40]. Furthermore, it has been suggested that the CFTR may regulate membrane PL composition. In human airway epithelial cultured cells, the incorporation of fatty acids (FAs) into membrane PLs is decreased when chloride conductance channels are chemically blocked . A defective CFTR reduces the incorporation of linoleic acid in the PL of CF cells and transfecting these cells with the normal gene increases linoleic acid incorporation . Thus, a relationship is possible between chloride transport conductance and EFA metabolism. To date, these studies are limited and additional investigation is needed to establish the role of the chloride channel function in EFA movement and metabolism.
CFTR knock-out mice demonstrate EFAD. But the EFA composition of the cell membrane varies with different animal models. In cftr-/- mouse, the pancreas, lungs and ileum were deficient in (n-3) EFA , whereas in cftr tm1HGU/tm1HGU mice, the deficiency was in (n-6) EFA in plasma, lung and pancreatic PL . The PUFA differences between the two mouse models emphasize the importance of determining the exact composition of membrane PL from healthy men and CF patients according to genotype in order to tailor appropriate EFA nutritional intervention.
In CF, AA levels suggest that abnormal EFA status may result from an impaired EFA metabolism. High levels of AA are also reported in the cell membrane of the ileum of CFTR knock-out mice . The same AA imbalance has been reported in the PL fraction deriving from bronchial alveolar lavage fluid, plasma and tissues [31, 45–48] of CF patients. The increased AA level in tissues may result from either overproduction or diminished catabolism. In CF cells (CFPAC-1), the conversion of 18:2n-6 into 20:4n-6 by desaturation and elongation processes is enhanced 1.8-fold compared with CF cells transfected with the normal gene . AA overproduction is compatible with an intrinsic increase in AA release by CFTR-mutated respiratory epithelial cell lines . A decreased metabolism of AA through cyclooxygenase, lipooxygenase or cytochrome P450 pathways could also explain high levels of AA in tissues, but this hypothesis should be thoroughly tested in CF because of a) the high rates of inflammatory species originating from AA that characterize CF patients; and b) the enhanced turnover of endogenous and exogenous AA in polymorph neutrophil granulocytes, which is possibly due to enhanced phospholipase A2 (PLA2) activity . Then, AA catabolism is not obviously diminished, but the ratio between production and degradation may be unbalanced in favor of overproduction. Accordingly, it has been suggested that AA participates in CF physiopathology, since AA has been shown to inhibit CFTR Cl- currents when applied to the cytoplasmic face of excised membrane patches [51, 52]. Other FAs may also block CFTR pores with various levels of efficiency. For example, cis-unsaturated FAs are more effective than trans-unsaturated FAs and saturated FAs in interfering with CFTR function . Furthermore, in respiratory epithelial cells, CFTR mutation ΔF508 is associated with an intrinsic increase in AA release  suggesting that the mechanism of chronic inflammation in CF, at least in part, involves this abnormality. Importantly, Chlore ion (Cl-) secretion across epithelial cells is induced by AA [53, 54]. On the other hand, AA decreases Cl- secretion across tracheal epithelium when its metabolism is impaired by cyclooxygenase and lipooxygenase inhibitors  suggesting that enhanced Cl- secretion results from the action of its metabolites . Furthermore, there is a correlation between EFAD and CF genotype in homozygotes for ΔF508 and heterozygotes for 394 delTT have displayed significantly lower concentrations of linoleic and DHA than the other mutations . Thus, the relationship between AA metabolism abnormalities and specific mutations may explain the discrepancies observed with n-6 EFA supplementation [19, 22, 56–58]. Evidently, extensive studies are required to clarify the link between the CFTR and FAs, especially in view of the contribution of EFAD to CF pathophysiology.
In animals, EFAD induces symptoms similar to those in CF: defective Na+ transport, increased bacterial colonization of airways, formation of clusters of lipid-laden macrophages in lungs , impaired alveolar macrophage function , alteration of surfactants , liver steatosis, decreased insulin secretion and increased caloric needs . Interestingly, a membrane lipid imbalance plays a role in the phenotype expression in CFTR knock-out mice and feeding these animals with DHA has normalized disease-related changes that occur in epithelial cells and intestinal mucosa .
Of note is the finding that altered PL composition and structure can impair membrane fluidity [64–66], thereby modifying CFTR cell membrane localization and function. Membrane PL composition in CFTR knock-out mice is different from controls . Apparently, lipid membrane composition regulates membrane protein activity through the association between lipid rafts and these proteins . The transient residency of proteins in rafts emerges as a regulatory mechanism responsible for protein biological activity. Recently, it has been reported that lipid raft localization for CFTR is required for signaling in response to Pseudomonas aeruginosa infection, underlying the interaction between the lipid composition of plasma membrane and the CFTR protein . It seems, therefore, that a correction of PL composition may improve CFTR activity in vivo, a hypothesis that calls for direct experimental validation in intestinal cells.
II.3. Nutritional Status and Prognosis in CF
Various studies emphasize a correlation between a low nutritional status and an unfavorable prognosis in patients with CF . Chronic undernutrition is associated with weight and height retardation in CF children. Early studies showed a correlation between the degree of malnutrition and the severity of pulmonary disease [69–71] and a slower rate of deterioration of pulmonary function was found in CF children without steatorrhea . However, low values of EFA (linoleic acid and DHA) are not always correlated with anthropometric data or lung function . CF survival and well-being are also correlated with malnutrition in CF . This positive correlation between good nutritional status and long-term survival underscores the optimization of energy balance, nutrient intake, as well as intestinal absorption for CF patients.
Since EFA levels are abnormal in CF patients and EFAD may contribute to CF pathophysiology in animal models, it has been suggested that EFA supplementation has a beneficial effect in this disease. Nutritional studies demonstrate that oral and intravenous supplementations with n-3 FAs are efficient in increasing EPA and DHA incorporation in plasma, erythrocyte and platelet membrane. [56–58]. Oral supplementation with n-6 FAs increases plasma and erythrocyte membrane AA levels [22, 74–76]. The clinical effects of EFA supplementation vary among studies: linoleic acid increases weight for height in CF children [19, 22] and an improvement in pulmonary function is also observed with n-3 FA intake. Nevertheless, this valuable effect is not reported in all studies. [56–58] and the differences may be explained by the limited number of patients (under 20) and the short duration (between 4 and 6 weeks) that prevent the proper evaluation of any clinical benefit. Undoubtedly, further studies should focus on the relationship between dose recommendations, the degree of correction of plasma EFAs and clinical outcome. In particular, long-term lipid dosage adjustments are necessary to define the optimal n-3/n-6 ratio required in CF patients to prevent clinical manifestations.
In contrast to carbohydrates and proteins, lipids are poorly soluble in water. Their lipolysis into the aqueous phase of the intestinal lumen, as well as their transport into plasma, requires the formation of soluble complexes such as BAs and lipoproteins (LPs). Any deficiency or variation in these processes may impact on fat digestion and transport. Fat malabsorption in CF may result from the inefficiency of sequential events: the lipolysis of alimentary lipids, the effect of BAs on micellar solubilization, the integrity of intestinal mucus and enterocytes, multiple intracellular processes and LP secretion. These lipid digestive and absorptive steps will be discussed chronologically.
III. Intraluminal Abnormalities
III.1.1. Lipolytic Phase
TGs cannot be transported into the cell because of their size and their hydrophobic characteristics. The lipolysis process is required to produce smaller and more hydrophilic molecules, which can thus be absorbed. TGs can be hydrolyzed by two lipolytic enzymes in humans: gastric lipase and pancreatic lipase [77, 78]. The enzyme postulated to be the main participant in gastrointestinal lipid digestion is pancreatic lipase. However, intra-gastric lipolysis accounts for about 20–30% of total gastrointestinal lipolysis in vivo and it has been suggested that it is increased in CF pancreatic insufficiency.
III.1.1 Gastric Lipase
Human gastric lipase is the key acid enzyme that is secreted by the chief cells located in the fundic region of the stomach. Human gastric lipase is stable in gastric juice at pH values ranging from 2.0 to 7.0 and is the most stable acid lipase .
In the past, it was suggested that gastric lipase played only a minor role in the digestion of dietary fat, because of its specificity for medium-chain FAs, which are less common than long-chain FAs in dietary fat . In fact, human gastric lipase also exerts an important activity on long-chain TGs in an acidic pH. When pH levels are between 5 and 6, it hydrolyzes medium-chain TGs more efficiently than longer ones . This lipase is quantitatively important, contributing 20–30% of TG acyl chain hydrolysis [82–84]. Moreover, initial digestion of dietary fat in the stomach was found to be an essential step for optimal intestinal lipolysis for three reasons: releasing long-chain PUFA in the stomach induces cholecystokinine output, which stimulates pancreatic lipase secretion ; the efficiency of pancreatic lipase is increased with partially hydrolyzed TGs ; and free fatty acids (FFAs) enhance lipase binding to colipase .
Acid lipase activity exists in CF children [87, 88], but its level, compared with normal controls, varies among studies [89, 90]. Basal lipase activity in the stomach and in the duodenum is similar in CF patients and normal controls , but its lipolytic activity is almost three times higher in CF patients after a test meal . There are two main explanations for the maintained high activity of acid lipase in CF patients. First, contrary to pancreatic lipase, the low postprandial pH in the upper small intestine, due to bicarbonate deficiency, does not inactivate gastric lipase activity [92, 93] and the latter is preserved for a longer period than in normal subjects. Second, the inactivation of gastric lipase is less effective, because of the low concentration of BAs and pancreatic proteolytic enzymes [94, 95]. Compensatory lipolytic activity by gastric lipase may account for 40–70% of dietary fat digestion [87, 96]. In CF patients, preduodenal activity amounts to 90% of the total lipase activity at the ligament of Treitz in the postprandial state . However, acid-resistant enzyme supplements, such as fungal lipase, fail to prove efficacy in CF . No correlation between gastric lipase and EFA status is reported in the literature.
III.1.2. Pancreatic Lipase and Colipase
Amphipathic molecules, monoacylglycerols (MG) and FA, produced during TG hydrolysis, stabilize dietary fat emulsion. Most of the fat digestion occurs in the upper small intestine following the action of pancreatic lipase and BAs. The hydrolysis of long-chain TGs is achieved by pancreatic lipase. Its optimum pH is 8 and the enzyme becomes inactive at a pH under 6 and is irreversibly inactivated at a pH less than 4.5. Colipase is required for pancreatic lipase stabilization on lipid droplets and for optimal lipolytic activity. At least, two other hydrolytic enzymes are needed to release FAs: PLA2 and cholesterol esterase (CET).
Fat malabsorption is present only when pancreatic enzyme secretion is under 10% of normal . On diagnosis, only 15% of CF patients have sufficient pancreatic function for normal fat digestion . The pancreatic function decreases with time, since 37% of CF newborns show a substantial preservation of pancreatic function  and more than 90% of CF infants and younger children display pancreatic insufficiency. The physiopathology of pancreatic insufficiency results from several abnormalities. In fact, pancreatic changes are caused by the obstruction of small ducts by thick, sticky secretions and cellular debris. A primary defect of fluid secretion (water and bicarbonate) leads to high protein concentration in pancreatic juice . Then, protein precipitation blocks small pancreatic ducts and promotes pancreatic acinar atrophy and fibrosis. The ratio of acinar cells to connective tissue decreases progressively in the pancreas of CF children until the normal structure of the pancreas is lost. The role of the CFTR for normal proliferation and differentiation of secretory cell populations has been demonstrated in the lung and intestine of transgenic mice [101, 102] and, interestingly, the CFTR appears as a valuable marker of human pancreatic duct cell development and differentiation . CFTR mutation may, therefore, affect the proliferation of pancreatic secretory cells, thereby favoring pancreatic insufficiency and physiopathology.
Not only quantitative but also qualitative abnormalities characterize pancreatic lipase activity. Pancreatic lipase supplements are inactivated by acidic pH levels in the small bowel: only 8% of active enzyme reaches the ligament of Treitz [92, 93]. The severity of pancreatic involvement appears to increase with age and, even with maximum pancreatic enzyme replacement therapy, a substantial proportion of ingested energy is probably malabsorbed.
There is little information about colipase in CF. Although, colipase has been reported to be deficient in this disease , its secretion is extremely variable in CF patients . More investigations are necessary to clarify this aspect.
End products of gastric lipases are mainly one FFA and one 1-3-diacylglycerol, while the lipolytic products of pancreatic lipase are two FFAs (Sn-1 and Sn-3 postions) and one 2-monoacylglycerol . Furthermore, in contrast to pancreatic lipase, gastric lipase has been shown to cleave not only the external ester bonds (n-1 and n-3 position), but also the ester bond in the Sn-2 position . This difference is important for nutritional intervention with enteral defined structured TGs, which provide medium-chain FA as a source of immediate energy. In Caco-2 cell cultures, the addition of structured TGs containing only octanoic acid, a non-EFA, in the Sn-1 and Sn-3 position, but linoleic acid in the Sn-2 position in the presence of gastric lipase, enhances the cellular uptake of TGs, improves cellular EFAD and exhibits a beneficial effect on lipid incorporation and LP production . In the rat, EFAs at the Sn-2 position appear faster in lymph than EFAs at the terminal positions of TGs  and are more readily recovered in lymph . Defined TG with EFA linoleic acid at the Sn-2 position increases the absorption of EFA in rats with fat malabsorption induced by biliary and pancreatic diversion . These results suggest that structured TG, in the presence of gastric lipase, could improve EFAD, despite the absence of pancreatic lipase activity. In patients who are not supplemented with pancreatic enzymes, an organized lipid matrix containing lysophosphatidylcholine (Lyso-PC), MG and FFA could be effective in increasing TG and retinyl-palmitate absorption and in improving clinical outcome .
In animal models, EFAD does not affect the lipolytic phase: there is no difference between EFAD and control rodents in the lipolytic step [113, 114]. Furthermore, animal models suggest that EFAD is likely to be of minor importance in exocrine pancreas function in CF [113, 115]. Furthermore, EFAD does not seem to induce any significant changes in the structure and composition of pancreas . Overall, these studies show that structured TG can effectively supply functional FAs distributed throughout the glycerol skeleton. In particular, structured TG with EFAs at the Sn-2 position and medium chain FAs at the Sn-1 and Sn-2 positions of the glycerol molecule can be used for distinct nutritional and clinical purposes in CF. Although, it is obvious that structured TG are far superior to conventional oils, it is quite difficult to appreciate their influence on lipolysis in CF patients with EFAD in view of the paucity of information available in the literature. Probably, the difficulty originates from the enormous cost of producing highly purified structured TG.
III.1.3. Phospholipase A2 (PLA2) and Cholesterol Esterase (CET)
The phospholipid-hydrolyzing enzymes include phospholipase A1 (PLA1), PLA2 and CET . PLA1 and PLA2 are secreted in their zymogen form and activated by trypsin on entering the duodenum . PLA2 preferentially hydrolyzes FA in phosphatidylcholine (PC), the most abundant dietary PL, at position 2 to produce more hydrosoluble components (FA and 2-lyso-PC). CET hydrolyzes CE, retinyl ester and lyso-PC in the small bowel , but it is 100 times less effective than pancreatic lipase in the TG digestion process.
In CF patients, PLA1 and PLA2 activity is correlated with the pancreatic function . It is of particular interest to note that, despite the total absence of PLA2, around 30% of PLs are hydrolyzed . The decreased activity of PL hydrolyzing enzymes may interact with lipid absorption in several ways. First, since PLs are amphipathic molecules, they adsorb to the surface of lipid droplets, preventing contact between the lipase-colipase complex and the TG substrate . PC hydrolysis will allow desorption of lyso-PL from lipid droplets, which are relatively hydrosoluble molecules, and will thus facilitate the interaction between TG and pancreatic lipase. Secondly, unhydrolyzed PLs impair the absorption of cholesterol and FAs [121, 122]. Finally, they impair bile acid absorption through their receptors in the terminal ileum, which increases bile acid losses in the stool.
In CF children, CET activity is dramatically decreased  and parallels pancreatic lipase activity. The reduction in BAs, which are essential cofactors for optimal esterase activity, results in a failure to solubilize and thus absorb cholesterol and their esters.
In the enterocyte, lyso-PC is an essential source of PLs for LP formation , the transport of TGs from the enterocyte into the blood  and the PL turnover induced by exocytosis . These phenomena may be impaired by phospholipase or CET defects.
No data are provided about the impact of EFAD on PLA1, PLA2 and CET activity. However, AA and DHA decrease the secretion of bile-salt dependent lipase, but without directly impairing the biosynthesis of this enzyme. AA alters the transport of the enzyme toward the cytosol, leading to the retention of bile-salt dependent lipase in microsomes . It is likely that much attention must be paid to phospholipases and CET in CF in view of their role in fat absorption. Future studies should be designed to test whether their supplementation may increase lipolysis efficiency and alleviate EFAD in CF.
III.1.4. Intraluminal pH
Duodenum pH results from an interaction among food buffering, gastric acid production and pancreatic bicarbonate secretion. In humans, physiological pH is 2–4 in the stomach and it varies from 6–7 in the upper duodenum, but rarely dips below 5.
In CF patients, pancreatic, intestinal and biliary HCO3- secretion is decreased to below 10% of the normal values . Consequently, a low pH is observed in the intestinal lumen of the duodenum and even during postprandial time. Besides, basal and postprandial pH levels in the stomach are similar in CF patients and normal subjects [91, 96]. In CFTR(-/-) mouse intestine, HCO3- secretion is impaired too [129, 130]. The acidic upper small intestine in CF may contribute to fat malabsorption given: 1) the inactivation of trypsin, which induces an impairment of active enzyme molecules from their zymogen form (pancreatic lipase, PLA2); 2) the inactivation of pancreatic lipase ; 3) BA precipitation, decreasing the BA pool and diminishing its availability to form micelles; and 4) early protonation, which impairs the micellar dispersion of lipolytic products . The ability of acid suppressant therapy (cimetidine, ranitidine or proton pump inhibitors) to improve fat absorption is controversial. Recently, a metanalysis of randomized trials involving agents that reduce gastric acidity has been carried out and it showed that treatment failed to improve nutritional status and had little impact on fat absorption . Differences between studies could be due to the small number of subjects, differences in dietary intake and the degree of pancreatic insufficiency, the important physiologic range in fat intestinal absorption and variability in intestinal drug absorption or interindividual variation in medication bioavailability, pH measurement and fat absorption evaluation.
III.2. Micellar Phase and Biliary Abnormalities
BAs are amphipathic molecules synthesized by the liver. They enhance the solubility of lipolytic products in the aqueous intestinal phase [134, 135]. In fact, micellar solubilization increases the aqueous concentration of MG and FA 100 to 1000 times. The importance of this phase is underscored by a 30% reduction in dietary lipid absorption in patients with biliary atresia . Similarly, rats with biliary drainage displayed reduced linoleic acid absorption .
III.2.1. BA Excretion
Outside the critical micellar concentration range, the amount of lipid solubilized is significantly reduced. Consequently, steatorrhea appears  and FA absorption decreases . This situation is found in CF patients where total bile salt secretion is impaired . About 36% of CF children showed reduced BA secretion into the duodenum . Despite this low BA secretion, impaired water secretion leads to high concentrations of bile salts in hepatobiliary secretions , which may contribute to the cholelithiasis reported in CF patients [94, 143].
EFAs regulate BA excretion: PUFAs are reported to induce the excretion of BA in rats  and humans , but this effect depends on the EFA family, since n-3 FA increases bile flow more than n-6 FA . The EFAD effect on bile flow and BA secretion varies among animal species: decreasing in rats [147, 148], having no effect in mice  and increasing in hamsters . In humans, the impact of EFAD on BA secretion and composition remains unclear. However, prostaglandins, which are AA metabolites, alter hepatic bile flow  indicating that disturbances of AA status may affect choleretic response in CF patients.
III.2.2. BA Composition
The nature of BAs influences their ability to solubilize lipids. Cholesterol absorption by enterocytes is greater with cholyl-taurine than with chenodeoxycholyl-taurine [150–152] and BAs with conjugated taurine are more effective than glycine-conjugated BAs at solubilizing lipids. The effect of EFA on BA composition variation and fat absorption remains enigmatic in humans, since there are no available data.
In CF, oral taurine load appears to be normal, but excessive fecal loss  increases the ratio of glycine/taurine-conjugated BA [94, 140, 141]. Oral taurine supplementation in CF children is effective in decreasing the glycine/taurine ratio in duodenal fluid , but its ability to improve fat malabsorption is controversial [154–157]. Apparently, taurine supplementation improves BA malabsorption, mainly in patients with a high degree of steatorrhea [158–160].
Studies on animals show that EFAD leads to impaired biliary excretion of taurocholate  and to reduced EFA content (linoleic and arachidonic acid) in biliary PC that is essential for micelle formation . However, BA and bile lipid composition vary across species. In rats and hamsters with EFAD, bile composition is markedly impaired [147, 161]. On the other hand, BA composition appears to be similar in EFA-deficient and EFA-sufficient mice .
The relationship between BA and EFA was investigated in CF-EFAD children and it showed that ursodeoxycholic acid supplementation improves the hepatic metabolism of EFA. After 1 year, ursodeoxycholic acid supplementation led to an improvement of EFA status (reduction of triene/tetraene FA ratio) .
III.2.3. BA Malabsorption
BAs are recycled through the enterohepatic cycle with remarkable efficiency (95% reabsorbed) [164, 165]. The enterohepatic cycle is often interrupted in CF because of excessive fecal losses of BA, [95, 166–170], which diminish the BA pool [171, 172]. Excessive BA losses may be attributed to: 1) BA irreversibly bound to unhydrolyzed TG and PL within the intestinal lumen  ; 2) BA precipitation due to acidic pH in the duodenum ; and 3) intestinal bacterial overgrowth, which is present in 40% of CF patients and results in BA deconjugation and dehydratation . BA loss may also result from a primary cell defect in the active absorption of BA in the ileum. In vitro studies using brush border membrane vesicles from CF patients have shown that total ileal BA uptake is diminished [176, 177]. Surprisingly, a study of Ileal Biliary Acid Transporter (IBAT) in CFTR knock-out mice shows a BA uptake rate four-fold that of wild-type mice . The increase in IBAT protein and BA uptake can be interpreted as an up-regulation in response to a low BA rate. This result should lead to a renewed interest in intraluminal events, especially for the implication of the thick mucus barrier in CF pathophysiology.
III.3. Gastric and Intestinal Transit Time
Fat digestion begins in the stomach with the action of acid lipase. Following hydrolysis by gastric lipase, medium-chain FAs are partly absorbed by the stomach . Thus, the stomach plays an essential role in fat digestion, especially in pancreatic insufficiency .
In CF patients with pancreatic insufficiency, altered motility with an increase in gastric emptying  and small bowel transit time has been described [181–184]. It has been reported that slow gastric emptying reduces the success of pancreatic enzyme replacement therapy in improving TG hydrolysis, which could explain in part the variation in pancreatic enzyme replacement therapy efficiency [180, 185]. However, other studies have shown that gastric emptying time is similar in both CF patients and healthy controls [90, 182].
In EFAD rats, AA and linoleic acid are emptied from the stomach at similar rates and these rates do not differ from controls . However, EFA-deficient mice show that the motility of epithelial cells is increased in the jejunum .
III.4. Intestinal Mucosa Trophicity
III.4.1. Quantitative and Qualitative Mucosal Abnormalities
In the majority of CF patients, histological brush border studies reveal normal morphology . However, in some cases, abnormalities are reported, such as ileal hypertrophy  or partial villous atrophy in the small intestine [190, 191]. This atrophic mucosa, which also occurs in knock-out mice , may result from acidic aggression by unbuffered stomach chyme, chronic inflammation or denutrition. Furthermore, a thick mucinous layer covering the brush border and large areas of the microvilli is revealed by electron microscopic examination of biopsies from CF patients , which may contribute to malabsorption in CF patients. The viscosity of the intact CF glycoprotein is almost two-fold that of normal glycoprotein . Elevated viscosity may be caused by defective chloride transport, mucin hyperglycosylation or a high level of disulfide-linked peptides [193, 194]. Obviously, the highly acidic properties of surface components related to oversulfatation could modify the micro acidic climate on the intestinal epithelium surface and influence interaction between micelles and enterocytes, impairing the protonation of FAs.
In EFAD, histological and biochemical alterations of the intestinal mucosa are described . In rats and mice with EFAD, the height of villi is decreased leading to a diminished absorption area. Cellular differentiation was also found to be impaired , highlighting the role of EFA in the formation of new tissues, such as the maintenance of tissue and cell structure . Furthermore, the abnormal structure of mitochondria and microvilli is correlated to decreased fat absorption . It seems difficult to reconcile jejunal hypertrophy in CF patients and microvilli in EFAD animals. However, EFAD seems to induce histological abnormalities in the CFTR function. In CFTR knock-out mice, jejunal hypertrophy is corrected with an oral administration of high doses of DHA , which are associated with an inhibitory proliferative cell effect . Then, more than in typical EFAD, an abnormal EFA imbalance could lead to hypertrophic villosities in CF patients. Hypertrophy is only localized in the jejunal portion. Accordingly, the FA composition of jejunum mucosa, the main segment for optimal lipid absorption, is markedly different from ileal and colonic mucosa . Furthermore, it is interesting to note that dietary influences are tissue specific, since serum or red blood cell membranes do not reflect local changes in any of the different intestinal segments . At present, no studies have correlated intestinal morphology in CF patients with their EFAD status.
III.4.2. Intestinal Permeability
Recently, studies have suggested that pathological modifications in EFAD may be the consequence of cell adhesion disorders .
In CF patients, the dual sugar permeability test  demonstrates that the paracellular pathway is more permeable to large molecules, while the passive transcellular uptake of small molecules is normal . Intestinal permeability in CF is related to patient genotype: patients homozygous or heterozygous for ΔF508 mutation exhibit significantly increased intestinal permeability compared with patients with unidentified genotypes or controls . Moreover, abnormalities in the tight junction, an essential structure for the control of intestinal permeability, have been reported in the intestinal epithelium of fetuses with CF .
EFAs are able to modify cells ultrastructurally and to alter intestinal permeability. In the culture of enterocytes from EFA-deficient CF, the lateral surfaces between cells are fairly straight, a consequence of the absence of complex interdigitations that play an essential intercellular cohesive role . Moreover, a reduction in the number of desmosomes has been reported in the intestinal tract of EFAD rats [59, 204]. Studies in endothelial cells suggest a possible mechanism of EFA-modulating cell adhesion. However, this EFA function has to be demonstrated in intestinal cells. In endothelial cells, some PUFAs such as γ-linolenic acid or EPA increase transepithelial electrical resistance and reduce paracellular permeability. Studies involving CF patients are definitely needed to assay intestinal cell adhesion molecules and their relation to FA status.
IV. Enterocyte Phase Abnormalities
IV.1. Enterocyte Lipid Uptake
EFAs may be absorbed by enterocytes, mostly in the form of EFA and MG. Until recently, it was assumed that these lipids diffused passively through the enterocyte brush border membrane . Indeed, earlier studies reported that the uptake of FAs occurred at 0°C, implying that the process is strictly passive. In particular, the intestinal absorption mechanism of linoleate was noted to depend on its intraluminal concentration, showing a passive diffusion at high concentrations. However, a transporter was required at weaker concentrations . Accordingly, the absorption of FFA was found to be a saturable phenomenon that can be inhibited through competition with long-chain PUFA . These observations suggest that FA uptake is a concentration-dependent dual transport mechanism involving both passive diffusion and a carrier-dependent process. Recently, several membrane transport systems have been identified and they seem to be involved in the enterocyte absorption of lipids: membrane FA binding protein (FABPm), capable of facilitating transmembrane passage mainly of FAs, but other lipids as well [208–210]; FA translocase/cluster determinant 36 (FAT/CD36) implicated in long-chain FA transport. [211–213]; scavenger Receptor class B type I (SR-BI) that plays a role especially in cholesterol movement (absorption and/or efflux) at the enterocyte level ; ATP Binding Cassette transporter family that provides several cholesterol carriers: ABCG5 and ABCG8 cooperate to limit sterol intestinal absorption, rather facilitating cholesterol efflux toward the intestinal lumen and their mutations predispose to sitostrolemia [215, 216]; and ABCA1 expressed in the enterocyte, which could partially control cholesterol efflux toward the intestinal lumen , although its exact role in the brush border membrane remains controversial [218, 219]. Recently, a new protein called Nieman Pick C1-Like1 was identified in the small intestine. It seems closely involved in intestinal cholesterol absorption, a pathway sensitive to sterol absorption inhibitors such as ezetimibe [220, 221].
IV.1.2. CFTR and Lipid Transporters
No study to our knowledge has investigated the interaction that may exist between the CFTR and these lipid transporters. Yet, the CFTR is known to modulate the activity of other carriers as well as certain ionic channels, for instance [37, 222]. The CFTR regulation of other intestinal ionic transporters is effectively diminished in CF patients . Furthermore, a microarray study on pulmonary tissue from knock-out CFTR mice shows that membrane transporters specific for ligands as different as glutamate, hormones or neurotransmitters have their expression influenced by CFTR . The completion of the same type of study on intestinal tissue would likely offer interesting tracks to target lipid transport proteins capable of being influenced by the CFTR. The large diversity of transporters interacting with the CFTR could lead to impairment in enterocyte lipid uptake and trafficking in CF, which would represent another cause for nutrient malabsorption.
The existence of anomalies in the enterocyte uptake to EFA is controversial. In effect, EFA intestinal absorption in patients does not always appear to be impaired. Some studies report that the rate of linoleic acid absorption is normal when pancreatic enzyme supplementation is given at sufficient doses . Apparently, even the presence of steatorrhea was not accompanied by diminished EFA absorption  and no correlation has been established between steatorrhea and EFAD in preadolescents with CF . On the other hand, a recent study has shown that patients undergoing pancreatic enzyme treatment display a reduction in the intestinal uptake of long-chain FAs . The differences between these studies may indicate either that the intestinal malabsorption does not in itself explain the EFA deficit or that the severity of CFTR mutation could influence the enterocyte absorption of lipids. Unfortunately, genotyping analysis has not been carried out in most of these investigations. Future developments will get to the bottom of these major unsolved questions by tracing the defects in enterocyte lipid uptake, the status of lipid transporters, the relationship with CFTR in CF patients and fat malabsorption.
IV.1.3. EFAD and Lipid Transporters
Early studies on EFAD did not notice an anomaly in the enterocyte transport of EFA [186, 196, 227]. However, these data have not been confirmed. The studies are somewhat outdated and the sensitivity of the techniques used may be called into question. Furthermore, several elements suggest that EFAD may be implicated, at least to some extent, in lipid intestinal malabsorption. Indeed, EFAD can affect the lipid composition of the enterocyte membrane and modify its fluidity, which may directly disturb the functioning of the transporters that can be found there. Moreover, some transporters like the SR-BI or CD36 could act as transporters, not directly, but by creating a special micro-environment in the neighbouring membrane lipids. This local change favors the transfer of their ligands . In this model, it appears very likely that a modification of the physiochemical properties of the membrane, as is the case in EFAD, may impact on the transporter lipid transfer abilities. EFAD could also influence these lipid transporters more directly. In effect, most of these transporters are regulated by long-chain FAs: the expression of the FABP and CD36 genes is increased by long-chain FAs ; the SR-BI protein is also regulated according to the type of long-chain FAs (unpublished personal data); and finally, the polyunsaturated FAs trigger a decrease in the ABCA1 protein, thereby reducing the basolateral efflux of cholesterol in human Caco-2 cells . This regulation could be drilled through a reduction in ABCA1 expression  or an increase in the degradation of the protein .
FAs can also act directly on the level of expression of the CFTR protein. In this way, a short-chain FA, the butyrate, increases CFTR expression significantly in animal epithelium cell cultures . It is interesting to note that this same FA modulates lipid synthesis, the biogenesis of apolipoproteins (apos) and the assembly of LP in the enterocyte . To our knowledge, there are no similar studies with long-chain FAs or EFAs. The potential role for the CFTR in all the enterocyte lipid synthesis steps underlines the need for new investigations, which may lead to new therapeutic strategies.
IV.2. Enterocyte Lipid Trafficking
After crossing the brush border membrane, the lipids must be processed by cytosolic proteins for their intracellular trafficking toward various compartments, including the endoplasmic reticulum (ER), where their reesterification may take place. However, the precise mechanisms behind this transport remain unclear. Certain transport proteins have been identified, but their roles often remain hypothetical: the Sterol Carrier Protein (SCP-2) and two cytosolic FABP capable of linking FA in particular, but also PL. According to our unpublished and preliminary data, intestinal-FABP (I-FABP), which is restricted to the intestine, could direct the FAs to membranes for lipid cycling or to a degradation pathway (peroxisome or mitochondria), whereas the liver-FABP (L-FABP), also found in the liver, could guide them to the ER to be assembled into LP. I-FABP and L-FABP bind differently according to lipid class, but both with a greater affinity for unsaturated FAs than saturated FAs.
IV.2.2. CFTR and Enterocyte Lipid Trafficking
No study has examined the interactions that can exist between the various proteins of the cytoplasmic transport of lipids and the CFTR. However, it has been clearly demonstrated that anomalies in CF exist in the intracellular movement of the CFTR itself. Various physiochemical conditions, such as low temperatures  or chemical agents , are able to increase the stability of the mutated CFTR protein and avoid its abnormal retention in the ER [236, 237]. The latter would, in part, be attributable to a defective interaction between the CFTR and certain PLs that play the role of lipid chaperones. Obviously, the mutation of ΔF508 causes the CFTR protein to lose its ability to bind preferentially with phosphatidylserine rather than with PC. The replacement of PC with non charged analogues in mutated cell cultures increases CFTR expression and the quantity of its mature form. Therefore, certain PLs through their lipid chaperone function seem important for the intracellular trafficking of the CFTR . Moreover, the invalidation of the CFTR initiates changes in gene expression as well as protein degradation via ubiquitin-dependent proteasome, which may modify several transport proteins . Overall, these studies support the concept that CFTR is modulated by PLs and indicate potential relationships between CFTR and other local transporters. Unfortunately, it remains unknown how EFAs contained in PLs directly alter the activity of CFTR and whether a "partnership" exists between CFTR and intracellular lipid transporters in the enterocyte. Forthcoming investigations will highlight new links between the CFTR, EFAs and cellular processes, which may identify important factors that play a role in networks of lipid signalling and transport.
IV.2.3. EFA and Enterocyte Lipid Trafficking
The assembly of microtubules is critical for intracellular trafficking and chylomicron transport [239, 240]. Early reports had indicated that the administration of microtubule inhibitors led to a decrease in the conveyance of radioactive lipids in rat enterocytes . Certain EFAs, such as γ-linoleic acid or AA, regulate the microtubule polymerization [242, 243]. Thus, EFAD could hinder intraenterocyte trafficking through an alteration of microtubule polymerization, synthesis or function.
IV.3. Lipid Esterification and Lipoprotein Synthesis
The products of lipolysis once absorbed and transported to the ER are resesterified to form TG, PL and CE through specific enzymatic pathways. This reesterification involves several enzymes monoacylglycerol acyltransferase (MGAT), diacylglycerol acyltransferase (DGAT), glycerophosphate acyltransferase, phosphatidate phosphodiesterase, lyso-PC acyltransferase, CE and acyl-coenzyme A:cholesterol acyltransferase (ACAT). After their synthesis, hydrophobic lipids must be associated with proteins or apolipoproteins, in order to allow their solubilization in the blood circulation, thereby forming complexes known as LP. The intestine is capable of secreting most lipoprotein classes (chylomicrons, VLDL, HDL), but chylomicrons represent the specific and most abundant class in the enterocyte.
Note that apo B is a component that is essential for LP assembly and secretion by the intestine. It exists in two forms: apo B-100, present particularly in the liver, but to a limited extent in the intestine, and apo B-48, which is specific to the enterocyte that results from the posttranscriptional modification of the apo B-100 mRNA, or editing, involving an enzymatic complex called APOBEC-I (apo B mRNA-editing catalytic subunit-1) . Other apos are produced in the enterocyte, mainly apo A-I and apo A-IV that is exclusively of intestinal origin in humans . During its synthesis in the ER, apo B must undergo lipidation that protects it from degradation by the proteasome . Lipid transfer from the endoplasmic reticulum to apo B requires microsomal triglyceride transfer protein (MTP) intervention. This step is crucial for chylomicron assembly as noted in abetalipoproteinemia, an illness brought on by the mutation of the MTP gene, where there is defective lipoprotein secretion .
Pre-chylomicrons are exported to the Golgi apparatus where they undergo their final maturation (glycosylation of the apos, modification of certain PLs, etc.) before being secreted through the basolateral membrane into the lymphatic milieu. It is important to note the role of cargo proteins in the secretion step, which has been highlighted in chylomicron retention disease: the mutation of the Sar-1 GTPase protein prevents the secretion of chylomicrons through the dependent COPII vesicles . TG transfer from the ER to the Golgi apparatus seems to be a limiting step in fat absorption . After being secreted into the lymphatic capillaries, intestinal LPs are discharged into the systemic blood circulation through the thoracic canal.
IV.3.2. Role of the CFTR in the Intracellular Phase
In CF patients, lipid composition, concentration and size are irregular . At present, the role played by CFTR anomalies is unknown. To our knowledge, no study has focused on the possible interactions of the CFTR with the implicated enzymes in lipid reesterification, apo B biosynthesis, MTP activity or the relationship with Sar-1 GTPase protein expression.
It is during this LP secretion step that interactions with the CFTR may be the most likely. In fact, CFTR mutations alter the secretion not only of electrolytes, but also of substances as different as BAs by the hepatocyte , γ-light chain antibodies by lymphocytes , INFγ by monocytes  or neurotransmitters by pulmonary neuroendocrine cells . Since the enterocyte represents a key cell in the physiopathology of CF and given the numerous lipid aberrations observed in this disease, it appears essential to study the secretion abilities of lipids by epithelial cells instead of focusing only on the digestive mechanism in CF as is presently the case. For example, the recent analysis of RNA, influenced by CFTR knock-out, identified a number of proteins involved in LP metabolism, including proteasome 26S . The latter subunit is the major proteolytic component of the ubiquitin-dependent proteasome. As mentioned before, the ER-localized ubiquitin-proteasome pathway is primarily involved in the intracellular degradation of apo B. Its alteration in the absence of CFTR  indicates potential relationships between CFTR and the apo B recovery/degradation pathway, thereby determining LP assembly and secretion. Furthermore, there is increasing evidence that CFTR regulates endosomal fusion and vesicular trafficking , indicating potential relationships between the CFTR and ADP-ribosylation factor , which has a central role in VLDL assembly . Finally, the Sar-1/COPII complex is necessary when apo B-100 exits the hepatic ER  and apo B-48 containing chylomicrons are exported from the enterocyte . However, the Sar-1/COPII complex is also implicated in the exiting of CFTR from the ER  for its entry into the proteasome degradation pathway . Overall, these observations demonstrate the existence of possible interactions among apo B elaboration, chylomicron packaging and CFTR function. Hence, CFTR mutations may significantly affect lipid transport and obviously studies are needed to clarify this relationship.
IV.3.3. Possible Implications of EFAs in Intracellular Lipid Transport
It is important to underline that the anomalies in the reported LP during CF are most marked in patients with EFAD . These defects may either be the direct consequence of EFAD on LP synthesis or may only reflect an association between the type of CFTR mutation and lipid metabolism. A phenotypic classification of LP profiles according to genotype would allow us to elucidate this question. In fact, EFAD could cause interference at several levels within the process of LP synthesis and secretion.
TG reesterification rates are diminished in rats during EFAD [259, 260]. Lipid membrane modifications, notably long-chain FAs, are known to change the functioning of reesterification key enzymes such as MGAT . Similarly, intake rich in (n-3) FA lowers the ratio (n-6)/(n-3) and leads to an activation of DGAT and ACAT . Therefore, an unbalancing of the EFA status could affect the lipid reesterification step.
Biosynthesis through the enterocytes of several apos, such as apo B or apo A-IV, is regulated in a specific way by certain EFAs [263–265]. Experimental studies confirm investigations carried out on humans . Thus, EFAD is possibly deleterious for the synthesis of the main intestinal LP. Accordingly, enterocyte secretion of synthesized lipids is impaired during EFAD in mice and rats, which translates into an accumulation of large lipid droplets in the intercellular space . Notably, in EFAD, the balance between the various EFAs rather than directly the absence of EFAs could impair the exocytosis mechanism. In effect, in enterocyte cultures, certain EFAs, such as EPA, decrease TG esterification and PL transfer from the ER to the Golgi and the mechanisms responsible for these processes have not yet been specified . Similarly, EFAD may affect microtubules [242-268], as we previously mentioned, which could impact on the assembly and secretion of chylomicrons [239, 240, 242].
It is well established that defective digestive processes in CF patients are secondary to pancreatic insufficiency. However, it is difficult to reconcile the failure of appropriate pancreatic enzyme replacement therapy with the persistent fat malabsorption. Since mutations in CFTR result in impaired intracellular pH organelle, glycosylation and sialylation in mammalian cells, it is possible that disturbances in intestinal CF lipid transport may also be associated with cause-related changes in the second step of fat absorption, i.e. the intracellular phase leading to lipolytic product uptake and esterification, apolipoprotein synthesis and processing, and nascent lipoprotein assembly and secretion following the fusion of Golgi vesicles with the basolateral plasma membrane. This hypothesis is reinforced by the findings that CFTR dysfunction alters further intracellular pathways, crucial for lipoprotein packaging and delivery, such as ubiquitin-proteasome complexes, endosomal fusion and vesicular trafficking, as well as Sar1/COP II and ADP-ribosylation factor 1/COP I systems. Additionally, in keeping with substantial growing evidence from the available literature, it is reasonable to put forward that EFAD contributes to CF malabsorption by interfering with intra-enterocyte lipid transport. If previous studies had entirely attributed EFAD to diminished EFA intake and malabsorption, it is likely today that a mutated CFTR may also decrease the incorporation of EFAs in PL , increases the release of AA , lowers the concentrations of linoleic acid and DHA, and disrupts EFA metabolism [42, 50]. An interrelation between CFTR and EFAs is demonstrated when the chloride channels are blocked chemically . Nevertheless, the exact relationship between CFTR and EFAs remains unclear and studies in this fundamental direction would shed considerable light on our understanding of the mechanisms responsible for EFAD in CF. This aspect is particularly important given the suggestions that EFAD is related to a basic defect in FA metabolism. It seems imperative that rigorous and long-term studies be conducted on EFA supplementation to normalize EFA status in CF patients, otherwise EFAD would continue to affect intestinal lipid transport and to simultaneously exacerbate the poor clinical course of the CF patients.
- AA (20:
4n-6): Arachidonic Acid
ATP Binding Cassette transporter A1
Acyl-coenzyme A:cholesterol acyltransferase
Cluster Determinant 36
Cystic Fibrosis Transmembrane Conductance Regulator
- DHA (22:
6n-3): Docosahexaenoic Acid
Essential Fatty Acid
Essential Fatty Acid Deficiency
- EPA (20:
5n-3): Eicosapentaenoic acid
Fatty Acid Binding Protein
Free Fatty Acids
Ileal Biliary Acid Transporter
Microsomal Triglyceride Transfer Protein
Polyunsaturated Fatty Acid
Scavenger Receptor class B type I
Smith AE: Treatment of cystic fibrosis based on understanding CFTR. J Inherit Metab Dis. 1995, 18: 508-516. 10.1007/BF00710062.
Anderson MP, Rich DP, Gregory RJ, Smith AE, Welsh MJ: Generation of cAMP-activated chloride currents by expression of CFTR. Science. 1991, 251: 679-682.
Bear CE, Li CH, Kartner N, Bridges RJ, Jensen TJ, Ramjeesingh M, Riordan JR: Purification and functional reconstitution of the cystic fibrosis transmembrane conductance regulator (CFTR). Cell. 1992, 68: 809-818. 10.1016/0092-8674(92)90155-6.
Drumm ML, Pope HA, Cliff WH, Rommens JM, Marvin SA, Tsui LC, Collins FS, Frizzell RA, Wilson JM: Correction of the cystic fibrosis defect in vitro by retrovirus-mediated gene transfer. Cell. 1990, 62: 1227-1233. 10.1016/0092-8674(90)90398-X.
Roy CC, Weber AM, Lepage G, Smith L, Levy E: Digestive and absorptive phase anomalies associated with the exocrine pancreatic insufficiency of cystic fibrosis. J Pediatr Gastroenterol Nutr. 1988, 7 Suppl 1: S1-S7.
Welsh MJ, Fick RB: Cystic fibrosis. J Clin Invest. 1987, 80: 1523-1526.
Carroccio A, Pardo F, Montalto G, Iapichino L, Soresi M, Averna MR, Iacono G, Notarbartolo A: Use of famotidine in severe exocrine pancreatic insufficiency with persistent maldigestion on enzymatic replacement therapy. A long-term study in cystic fibrosis. Dig Dis Sci. 1992, 37: 1441-1446. 10.1007/BF01296016.
Couper RT, Corey M, Durie PR, Forstner GG, Moore DJ: Longitudinal evaluation of serum trypsinogen measurement in pancreatic- insufficient and pancreatic-sufficient patients with cystic fibrosis. J Pediatr. 1995, 127: 408-413.
Kalivianakis M, Minich DM, Bijleveld CM, van Aalderen WM, Stellaard F, Laseur M, Vonk RJ, Verkade HJ: Fat malabsorption in cystic fibrosis patients receiving enzyme replacement therapy is due to impaired intestinal uptake of long-chain fatty acids. Am J Clin Nutr. 1999, 69: 127-134.
Kristidis P, Bozon D, Corey M, Markiewicz D, Rommens J, Tsui LC, Durie P: Genetic determination of exocrine pancreatic function in cystic fibrosis. Am J Hum Genet. 1992, 50: 1178-1184.
Zentler-Munro PL, Fine DR, Batten JC, Northfield TC: Effect of cimetidine on enzyme inactivation, bile acid precipitation, and lipid solubilisation in pancreatic steatorrhoea due to cystic fibrosis. Gut. 1985, 26: 892-901.
Posner BM, Cupples LA, Franz MM, Gagnon DR: Diet and heart disease risk factors in adult American men and women: the Framingham Offspring-Spouse nutrition studies. Int J Epidemiol. 1993, 22: 1014-1025.
Carey MC, Hernell O: Digestion and absorption of fat. Semin Gastrointest Dis. 1992, 3: 189-208.
Farrell PM, Mischler EH, Engle MJ, Brown DJ, Lau SM: Fatty acid abnormalities in cystic fibrosis. Pediatr Res. 1985, 19: 104-109.
Hubbard VS, Dunn GD, di Sant'Agnese PA: Abnormal fatty-acid composition of plasma-lipids in cystic fibrosis. A primary or a secondary defect?. Lancet. 1977, 2: 1302-1304. 10.1016/S0140-6736(77)90359-2.
Lepage G, Levy E, Ronco N, Smith L, Galeano N, Roy CC: Direct transesterification of plasma fatty acids for the diagnosis of essential fatty acid deficiency in cystic fibrosis. J Lipid Res. 1989, 30: 1483-1490.
Parsons HG, O'Loughlin EV, Forbes D, Cooper D, Gall DG: Supplemental calories improve essential fatty acid deficiency in cystic fibrosis patients. Pediatr Res. 1988, 24: 353-356.
Rosenlund ML, Kim HK, Kritchevsky D: Essential fatty acids in cystic fibrosis. Nature. 1974, 251: 719-
van Egmond AW, Kosorok MR, Koscik R, Laxova A, Farrell PM: Effect of linoleic acid intake on growth of infants with cystic fibrosis. Am J Clin Nutr. 1996, 63: 746-752.
Lloyd-Still JD, Bibus DM, Powers CA, Johnson SB, Holman RT: Essential fatty acid deficiency and predisposition to lung disease in cystic fibrosis. Acta Paediatr. 1996, 85: 1426-1432.
Benabdeslam H, Garcia I, Bellon G, Gilly R, Revol A: Biochemical assessment of the nutritional status of cystic fibrosis patients treated with pancreatic enzyme extracts. Am J Clin Nutr. 1998, 67: 912-918.
Steinkamp G, Demmelmair H, Ruhl-Bagheri I, von der HH, Koletzko B: Energy supplements rich in linoleic acid improve body weight and essential fatty acid status of cystic fibrosis patients. J Pediatr Gastroenterol Nutr. 2000, 31: 418-423.
Chase HP, Dupont J: Abnormal levels of prostaglandins and fatty acids in blood of children with cystic fibrosis. Lancet. 1978, 2: 236-238. 10.1016/S0140-6736(78)91746-4.
Roulet M, Frascarolo P, Rappaz I, Pilet M: Essential fatty acid deficiency in well nourished young cystic fibrosis patients. Eur J Pediatr. 1997, 156: 952-956. 10.1007/s004310050750.
Holman RT: The ratio of trienoic: tetraenoic acids in tissue lipids as a measure of essential fatty acid requirement. J Nutr. 1960, 70: 405-410.
Chan GM: Performance of dual-energy x-ray absorptiometry in evaluating bone, lean body mass, and fat in pediatric subjects. J Bone Miner Res. 1992, 7: 369-374.
Clandinin MT, Zuberbuhler P, Brown NE, Kielo ES, Goh YK: Fatty acid pool size in plasma lipoprotein fractions of cystic fibrosis patients. Am J Clin Nutr. 1995, 62: 1268-1275.
Lloyd-Still JD, Johnson SB, Holman RT: Essential fatty acid status in cystic fibrosis and the effects of safflower oil supplementation. Am J Clin Nutr. 1981, 34: 1-7.
Landon C, Kerner JA, Castillo R, Adams L, Whalen R, Lewiston NJ: Oral correction of essential fatty acid deficiency in cystic fibrosis. JPEN J Parenter Enteral Nutr. 1981, 5: 501-504.
Strandvik B, Bronnegard M, Gilljam H, Carlstedt-Duke J: Relation between defective regulation of arachidonic acid release and symptoms in cystic fibrosis. Scand J Gastroenterol Suppl. 1988, 143: 1-4.
Strandvik B, Svensson E, Seyberth HW: Prostanoid biosynthesis in patients with cystic fibrosis. Prostaglandins Leukot Essent Fatty Acids. 1996, 55: 419-425. 10.1016/S0952-3278(96)90125-8.
Rogiers V, Dab I, Michotte Y, Vercruysse A, Crokaert R, Vis HL: Abnormal fatty acid turnover in the phospholipids of the red blood cell membranes of cystic fibrosis patients (in vitro study). Pediatr Res. 1984, 18: 704-709.
Levy E, Roy C, Lacaille F, Lambert M, Messier M, Gavino V, Lepage G, Thibault L: Lipoprotein abnormalities associated with cholesteryl ester transfer activity in cystic fibrosis patients: the role of essential fatty acid deficiency. Am J Clin Nutr. 1993, 57: 573-579.
Lepage G, Kneepkens CM, Roy C: Dysfonction peroxysomiale associée à la déficience en acides gras essentiels. Médecine/Sciences. 1993, 9: 571-576.
Egan M, Flotte T, Afione S, Solow R, Zeitlin PL, Carter BJ, Guggino WB: Defective regulation of outwardly rectifying Cl- channels by protein kinase A corrected by insertion of CFTR. Nature. 1992, 358: 581-584. 10.1038/358581a0.
Guggino WB: Outwardly rectifying chloride channels and CF: a divorce and remarriage. J Bioenerg Biomembr. 1993, 25: 27-35. 10.1007/BF00768065.
Gabriel SE, Clarke LL, Boucher RC, Stutts MJ: CFTR and outward rectifying chloride channels are distinct proteins with a regulatory relationship. Nature. 1993, 363: 263-268. 10.1038/363263a0.
Barasch J, Kiss B, Prince A, Saiman L, Gruenert D, al Awqati Q: Defective acidification of intracellular organelles in cystic fibrosis. Nature. 1991, 352: 70-73. 10.1038/352070a0.
Bradbury NA, Jilling T, Berta G, Sorscher EJ, Bridges RJ, Kirk KL: Regulation of plasma membrane recycling by CFTR. Science. 1992, 256: 530-532.
Jilling T, Cunningham S, Barker PE, Green MW, Frizzell RA, Kirk KL: Genetic complementation in cystic fibrosis pancreatic cells by somatic cell fusion. Am J Physiol. 1990, 259: C1010-C1015.
Kang JX, Man SF, Brown NE, Labrecque PA, Clandinin MT: The chloride channel blocker anthracene 9-carboxylate inhibits fatty acid incorporation into phospholipid in cultured human airway epithelial cells. Biochem J. 1992, 285 ( Pt 3): 725-729.
Bhura-Bandali FN, Suh M, Man SF, Clandinin MT: The deltaF508 mutation in the cystic fibrosis transmembrane conductance regulator alters control of essential fatty acid utilization in epithelial cells. J Nutr. 2000, 130: 2870-2875.
Freedman SD, Katz MH, Parker EM, Laposata M, Urman MY, Alvarez JG: A membrane lipid imbalance plays a role in the phenotypic expression of cystic fibrosis in cftr(-/-) mice. Proc Natl Acad Sci U S A. 1999, 96: 13995-14000. 10.1073/pnas.96.24.13995.
Dombrowsky H, Clark GT, Rau GA, Bernhard W, Postle AD: Molecular species compositions of lung and pancreas phospholipids in the cftr(tm1HGU/tm1HGU) cystic fibrosis mouse. Pediatr Res. 2003, 53: 447-454. 10.1203/01.PDR.0000049937.30305.8A.
Carlstedt-Duke J, Bronnegard M, Strandvik B: Pathological regulation of arachidonic acid release in cystic fibrosis: the putative basic defect. Proc Natl Acad Sci U S A. 1986, 83: 9202-9206.
Freedman SD, Blanco PG, Zaman MM, Shea JC, Ollero M, Hopper IK, Weed DA, Gelrud A, Regan MM, Laposata M, Alvarez JG, O'Sullivan BP: Association of cystic fibrosis with abnormalities in fatty acid metabolism. N Engl J Med. 2004, 350: 560-569. 10.1056/NEJMoa021218.
Gilljam H, Strandvik B, Ellin A, Wiman LG: Increased mole fraction of arachidonic acid in bronchial phospholipids in patients with cystic fibrosis. Scand J Clin Lab Invest. 1986, 46: 511-518.
Stead RJ, Muller DP, Matthews S, Hodson ME, Batten JC: Effect of abnormal liver function on vitamin E status and supplementation in adults with cystic fibrosis. Gut. 1986, 27: 714-718.
Miele L, Cordella-Miele E, Xing M, Frizzell R, Mukherjee AB: Cystic fibrosis gene mutation (deltaF508) is associated with an intrinsic abnormality in Ca2+-induced arachidonic acid release by epithelial cells. DNA Cell Biol. 1997, 16: 749-759.
Keicher U, Koletzko B, Reinhardt D: Omega-3 fatty acids suppress the enhanced production of 5-lipoxygenase products from polymorph neutrophil granulocytes in cystic fibrosis. Eur J Clin Invest. 1995, 25: 915-919.
Anderson MP, Welsh MJ: Fatty acids inhibit apical membrane chloride channels in airway epithelia. Proc Natl Acad Sci U S A. 1990, 87: 7334-7338.
Linsdell P: Inhibition of cystic fibrosis transmembrane conductance regulator chloride channel currents by arachidonic acid. Can J Physiol Pharmacol. 2000, 78: 490-499. 10.1139/cjpp-78-6-490.
Barrett KE, Bigby TD: Involvement of arachidonic acid in the chloride secretory response of intestinal epithelial cells. Am J Physiol. 1993, 264: C446-C452.
Shiota M, Kurano Y, Mochizuki Y, Kimura K, Ohta M, Sugano T: Effects of nerve stimulation and zymosan on glycogenolysis in perfused livers from cold-exposed rats. Am J Physiol. 1992, 263: G353-G359.
Strandvik B, Gronowitz E, Enlund F, Martinsson T, Wahlstrom J: Essential fatty acid deficiency in relation to genotype in patients with cystic fibrosis. J Pediatr. 2001, 139: 650-655. 10.1067/mpd.2001.118890.
Henderson WRJ, Astley SJ, McCready MM, Kushmerick P, Casey S, Becker JW, Ramsey BW: Oral absorption of omega-3 fatty acids in patients with cystic fibrosis who have pancreatic insufficiency and in healthy control subjects. J Pediatr. 1994, 124: 400-408.
Katz DP, Manner T, Furst P, Askanazi J: The use of an intravenous fish oil emulsion enriched with omega-3 fatty acids in patients with cystic fibrosis. Nutrition. 1996, 12: 334-339. 10.1016/S0899-9007(96)80056-6.
Kurlandsky LE, Bennink MR, Webb PM, Ulrich PJ, Baer LJ: The absorption and effect of dietary supplementation with omega-3 fatty acids on serum leukotriene B4 in patients with cystic fibrosis. Pediatr Pulmonol. 1994, 18: 211-217.
Eynard AR, Cejas V, Silva R, Quiroga P, Munoz S: Histopathology of essential fatty acid-deficient mice. Nutrition. 1992, 8: 37-40.
Harper TB, Chase HP, Henson J, Henson PM: Essential fatty acid deficiency in the rabbit as a model of nutritional impairment in cystic fibrosis. In vitro and in vivo effects on lung defense mechanisms. Am Rev Respir Dis. 1982, 126: 540-547.
Galabert C, Filliat M, Chazalette JP: Fatty-acid composition of serum-lecithins in cystic-fibrosis patients without steatorrhoea. Lancet. 1978, 2: 903-10.1016/S0140-6736(78)91620-3.
Akpan JO, Hurley MC, Lands WE: Insulin and glucagon secretion in essential fatty acid deficient rats. Acta Diabetol Lat. 1981, 18: 147-156.
Daveloose D, Linard A, Arfi T, Viret J, Christon R: Simultaneous changes in lipid composition, fluidity and enzyme activity in piglet intestinal brush border membrane as affected by dietary polyunsaturated fatty acid deficiency. Biochim Biophys Acta. 1993, 1166: 229-237.
Gaggiotti G, Taus M, Spazzafumo L, Tesei M, La Rocca R, Mazzanti L: Modifications of functional and physico-chemical properties of rat ileal plasma membranes. Biochem Mol Biol Int. 1995, 35: 851-854.
Kaur M, Kaur J, Ojha S, Mahmood A: Dietary fat effects on brush border membrane composition and enzyme activities in rat intestine. Ann Nutr Metab. 1996, 40: 269-276.
Lucero HA, Robbins PW: Lipid rafts-protein association and the regulation of protein activity. Arch Biochem Biophys. 2004, 426: 208-224. 10.1016/j.abb.2004.03.020.
Kowalski MP, Pier GB: Localization of cystic fibrosis transmembrane conductance regulator to lipid rafts of epithelial cells is required for Pseudomonas aeruginosa-induced cellular activation. J Immunol. 2004, 172: 418-425.
Ramsey BW, Farrell PM, Pencharz P: Nutritional assessment and management in cystic fibrosis: a consensus report. The Consensus Committee. Am J Clin Nutr. 1992, 55: 108-116.
Kraemer R, Rudeberg A, Hadorn B, Rossi E: Relative underweight in cystic fibrosis and its prognostic value. Acta Paediatr Scand. 1978, 67: 33-37.
SPROUL A, Huang N: GROWTH PATTERNS IN CHILDREN WITH CYSTIC FIBROSIS. J Pediatr. 1964, 65: 664-676.
Gaskin K, Gurwitz D, Durie P, Corey M, Levison H, Forstner G: Improved respiratory prognosis in patients with cystic fibrosis with normal fat absorption. J Pediatr. 1982, 100: 857-862.
Corey M, McLaughlin FJ, Williams M, Levison H: A comparison of survival, growth, and pulmonary function in patients with cystic fibrosis in Boston and Toronto. J Clin Epidemiol. 1988, 41: 583-591. 10.1016/0895-4356(88)90063-7.
Dodge JA, Custance JM, Goodchild MC, Laing SC, Vaughan M: Paradoxical effects of essential fatty acid supplementation on lipid profiles and sweat electrolytes in cystic fibrosis. Br J Nutr. 1990, 63: 259-271.
Hubbard VS, McKenna MC: Absorption of safflower oil and structured lipid preparations in patients with cystic fibrosis. Lipids. 1987, 22: 424-428.
Christophe A, Robberecht E, Franckx H, De Baets F, van de PM: Effect of administration of gamma-linolenic acid on the fatty acid composition of serum phospholipids and cholesteryl esters in patients with cystic fibrosis. Ann Nutr Metab. 1994, 38: 40-47.
Hamosh M, Scanlon JW, Ganot D, Likel M, Scanlon KB, Hamosh P: Fat digestion in the newborn. Characterization of lipase in gastric aspirates of premature and term infants. J Clin Invest. 1981, 67: 838-846.
Roberts IM, Montgomery RK, Carey MC: Rat lingual lipase: partial purification, hydrolytic properties, and comparison with pancreatic lipase. Am J Physiol. 1984, 247: G385-G393.
Ville E, Carriere F, Renou C, Laugier R: Physiological study of pH stability and sensitivity to pepsin of human gastric lipase. Digestion. 2002, 65: 73-81. 10.1159/000057708.
Cohen M, Morgan RG, Hofmann AF: Lipolytic activity of human gastric and duodenal juice against medium and long chain triglycerides. Gastroenterology. 1971, 60: 1-15.
Liao TH, Hamosh P, Hamosh M: Fat digestion by lingual lipase: mechanism of lipolysis in the stomach and upper small intestine. Pediatr Res. 1984, 18: 402-409.
Carriere F, Barrowman JA, Verger R, Laugier R: Secretion and contribution to lipolysis of gastric and pancreatic lipases during a test meal in humans. Gastroenterology. 1993, 105: 876-888.
Armand M, Pasquier B, Andre M, Borel P, Senft M, Peyrot J, Salducci J, Portugal H, Jaussan V, Lairon D: Digestion and absorption of 2 fat emulsions with different droplet sizes in the human digestive tract. Am J Clin Nutr. 1999, 70: 1096-1106.
Armand M, Borel P, Dubois C, Senft M, Peyrot J, Salducci J, Lafont H, Lairon D: Characterization of emulsions and lipolysis of dietary lipids in the human stomach. Am J Physiol. 1994, 266: G372-G381.
Carey MC, Small DM, Bliss CM: Lipid digestion and absorption. Annu Rev Physiol. 1983, 45: 651-677. 10.1146/annurev.ph.45.030183.003251.
Patton JS: Gastrointestinal lipid digestion. Physiology of the gastrointestinal tract. Edited by: Johnson LR. 1981, New York, Raven Press, 1123-
Fredrikzon B, Blackberg L: Lingual lipase: an important lipase in the digestion of dietary lipids in cystic fibrosis?. Pediatr Res. 1980, 14: 1387-1390.
Moreau H, Sauniere JF, Gargouri Y, Pieroni G, Verger R, Sarles H: Human gastric lipase: variations induced by gastrointestinal hormones and by pathology. Scand J Gastroenterol. 1988, 23: 1044-1048.
Hamosh M: A review. Fat digestion in the newborn: role of lingual lipase and preduodenal digestion. Pediatr Res. 1979, 13: 615-622.
Roulet M, Weber AM, Paradis Y, Roy CC, Chartrand L, Lasalle R, Morin CL: Gastric emptying and lingual lipase activity in cystic fibrosis. Pediatr Res. 1980, 14: 1360-1362.
Abrams CK, Hamosh M, Hubbard VS, Dutta SK, Hamosh P: Lingual lipase in cystic fibrosis. Quantitation of enzyme activity in the upper small intestine of patients with exocrine pancreatic insufficiency. J Clin Invest. 1984, 73: 374-382.
DiMagno EP, Malagelada JR, Go VL, Moertel CG: Fate of orally ingested enzymes in pancreatic insufficiency. Comparison of two dosage schedules. N Engl J Med. 1977, 296: 1318-1322.
Meyer JH: The ins and outs of oral pancreatic enzymes. N Engl J Med. 1977, 296: 1347-1348.
Roy CC, Weber AM, Morin CL, Combes JC, Nussle D, Megevand A, Lasalle R: Abnormal biliary lipid composition in cystic fibrosis. Effect of pancreatic enzymes. N Engl J Med. 1977, 297: 1301-1305.
Weber AM, Roy CC, Morin CL, Lasalle R: Malabsorption of bile acids in children with cystic fibrosis. N Engl J Med. 1973, 289: 1001-1005.
Hamosh M: Lingual and gastric lipases. Nutrition. 1990, 6: 421-428.
Zentler-Munro PL, Assoufi BA, Balasubramanian K, Cornell S, Benoliel D, Northfield TC, Hodson ME: Therapeutic potential and clinical efficacy of acid-resistant fungal lipase in the treatment of pancreatic steatorrhoea due to cystic fibrosis. Pancreas. 1992, 7: 311-319.
DiMagno EP, Go VL, Summerskill WH: Relations between pancreatic enzyme ouputs and malabsorption in severe pancreatic insufficiency. N Engl J Med. 1973, 288: 813-815.
Waters DL, Dorney SF, Gaskin KJ, Gruca MA, O'Halloran M, Wilcken B: Pancreatic function in infants identified as having cystic fibrosis in a neonatal screening program. N Engl J Med. 1990, 322: 303-308.
Durie PR: The pathophysiology of the pancreatic defect in cystic fibrosis. Acta Paediatr Scand Suppl. 1989, 363: 41-44.
Cohen JC, Morrow SL, Cork RJ, Delcarpio JB, Larson JE: Molecular pathophysiology of cystic fibrosis based on the rescued knockout mouse model. Mol Genet Metab. 1998, 64: 108-118. 10.1006/mgme.1998.2683.
Larson JE, Delcarpio JB, Farberman MM, Morrow SL, Cohen JC: CFTR modulates lung secretory cell proliferation and differentiation. Am J Physiol Lung Cell Mol Physiol. 2000, 279: L333-L341.
Hyde K, Reid CJ, Tebbutt SJ, Weide L, Hollingsworth MA, Harris A: The cystic fibrosis transmembrane conductance regulator as a marker of human pancreatic duct development. Gastroenterology. 1997, 113: 914-919.
Gaskin KJ, Durie PR, Lee L, Hill R, Forstner GG: Colipase and lipase secretion in childhood-onset pancreatic insufficiency. Delineation of patients with steatorrhea secondary to relative colipase deficiency. Gastroenterology. 1984, 86: 1-7.
Blackberg L, Hernell O, Bengtsson G, Olivecrona T: Colipase enhances hydrolysis of dietary triglycerides in the absence of bile salts. J Clin Invest. 1979, 64: 1303-1308.
Borgstrom B: On the interactions between pancreatic lipase and colipase and the substrate, and the importance of bile salts. J Lipid Res. 1975, 16: 411-417.
Levy E, Goldstein R, Freier S, Shafrir E: Characterization of gastric lipolytic activity. Biochim Biophys Acta. 1981, 664: 316-326.
Spalinger JH, Seidman EG, Lepage G, Menard D, Gavino V, Levy E: Uptake and metabolism of structured triglyceride by Caco-2 cells: reversal of essential fatty acid deficiency. Am J Physiol. 1998, 275: G652-G659.
Ikeda I, Tomari Y, Sugano M, Watanabe S, Nagata J: Lymphatic absorption of structured glycerolipids containing medium-chain fatty acids and linoleic acid, and their effect on cholesterol absorption in rats. Lipids. 1991, 26: 369-373.
Brink EJ, Haddeman E, de Fouw NJ, Weststrate JA: Positional distribution of stearic acid and oleic acid in a triacylglycerol and dietary calcium concentration determines the apparent absorption of these fatty acids in rats. J Nutr. 1995, 125: 2379-2387.
Christensen MS, Mullertz A, Hoy CE: Absorption of triglycerides with defined or random structure by rats with biliary and pancreatic diversion. Lipids. 1995, 30: 521-526.
Lepage G, Yesair DW, Ronco N, Champagne J, Bureau N, Chemtob S, Berube D, Roy CC: Effect of an organized lipid matrix on lipid absorption and clinical outcomes in patients with cystic fibrosis. J Pediatr. 2002, 141: 178-185. 10.1067/mpd.2002.124305.
Levy E, Garofalo C, Thibault L, Dionne S, Daoust L, Lepage G, Roy CC: Intraluminal and intracellular phases of fat absorption are impaired in essential fatty acid deficiency. Am J Physiol. 1992, 262: G319-G326.
Werner A, Minich DM, Havinga R, Bloks V, Van Goor H, Kuipers F, Verkade HJ: Fat malabsorption in essential fatty acid-deficient mice is not due to impaired bile formation. Am J Physiol Gastrointest Liver Physiol. 2002, 283: G900-G908.
Hjelte L, Ahren B, Andren-Sandberg A, Bottcher G, Strandvik B: Pancreatic function in the essential fatty acid deficient rat. Metabolism. 1990, 39: 871-875. 10.1016/0026-0495(90)90135-Y.
Hjelte L, Strandvik B, Muller RM, Sagstrom S, Roomans GM: Essential fatty acid deficient rats in the study of cystic fibrosis: an X-ray microanalytical and ultrastructural study in chronically reserpinized rats. J Submicrosc Cytol Pathol. 1990, 22: 409-414.
Duan RD, Borgstrom B: Is there a specific lysophospholipase in human pancreatic juice?. Biochim Biophys Acta. 1993, 1167: 326-330.
Borgstrom B: Importance of phospholipids, pancreatic phospholipase A2, and fatty acid for the digestion of dietary fat: in vitro experiments with the porcine enzymes. Gastroenterology. 1980, 78: 954-962.
Nouri-Sorkhabi MH, Chapman BE, Kuchel PW, Gruca MA, Gaskin KJ: Parallel secretion of pancreatic phospholipase A(2), phospholipase A(1), lipase, and colipase in children with exocrine pancreatic dysfunction. Pediatr Res. 2000, 48: 735-740.
Weber AM, Roy CC: Intraduodenal events in cystic fibrosis. J Pediatr Gastroenterol Nutr. 1984, 3 Suppl 1: S113-S119.
O'Connor PJ, Loiudice TA, Bochenek W, Rodgers JB: Effect of diester and diether phosphatidylcholine on intestinal absorption of neutral and acidic sterols. Am J Dig Dis. 1978, 23: 316-320. 10.1007/BF01072413.
Saunders DR, Sillery J: Lecithin inhibits fatty acid and bile salt absorption from rat small intestine in vivo. Lipids. 1976, 11: 830-832.
Mathias PM, Harries JT, Muller DP: Optimization and validation of assays to estimate pancreatic esterase activity using well-characterized micellar solutions of cholesteryl oleate and tocopheryl acetate. J Lipid Res. 1981, 22: 177-184.
Clark SB: Chylomicron composition during duodenal triglyceride and lecithin infusion. Am J Physiol. 1978, 235: E183-E190.
Nilsson A, Borgstrom B: Absorption and metabolism of lecithin and lysolecithin by intestinal slices. Biochim Biophys Acta. 1967, 137: 240-254.
Tso P, Lam J, Simmonds WJ: The importance of the lysophosphatidylcholine and choline moiety of bile phosphatidylcholine in lymphatic transport of fat. Biochim Biophys Acta. 1978, 528: 364-372.
Petit-Thevenin J, Bruneau N, Nganga A, Lombardo D, Verine A: Effects of arachidonic and docosahexaenoic acids on secretion and degradation of bile salt-dependent lipase in AR4-2J cells. J Lipid Res. 2001, 42: 1220-1230.
Sinaasappel M, Bouquet J, Neijens HJ: Problems in the treatment of malabsorption in CF. Acta Paediatr Scand Suppl. 1985, 317: 22-27.
Clarke LL, Harline MC, Gawenis LR, Walker NM, Turner JT, Weisman GA: Extracellular UTP stimulates electrogenic bicarbonate secretion across CFTR knockout gallbladder epithelium. Am J Physiol Gastrointest Liver Physiol. 2000, 279: G132-G138.
Seidler U, Blumenstein I, Kretz A, Viellard-Baron D, Rossmann H, Colledge WH, Evans M, Ratcliff R, Gregor M: A functional CFTR protein is required for mouse intestinal cAMP-, cGMP- and Ca(2+)-dependent. J Physiol. 1997, 505 ( Pt 2): 411-423. 10.1111/j.1469-7793.1997.411bb.x.
Robinson PJ, Smith AL, Sly PD: Duodenal pH in cystic fibrosis and its relationship to fat malabsorption. Dig Dis Sci. 1990, 35: 1299-1304. 10.1007/BF01536423.
Regan PT, Malagelada JR, DiMagno EP, Go VL: Reduced intraluminal bile acid concentrations and fat maldigestion in pancreatic insufficiency: correction by treatment. Gastroenterology. 1979, 77: 285-289.
Ng SM, Jones AP: Drug Therapies for Reducing Gastric Acidity in People with Cystic Fibrosis. Edited by: Wiley JS. 2004, Chichester, UK, 1-21.
Westergaard H, Dietschy JM: The mechanism whereby bile acid micelles increase the rate of fatty acid and cholesterol uptake into the intestinal mucosal cell. J Clin Invest. 1976, 58: 97-108.
Wilson FA, Sallee VL, Dietschy JM: Unstirred water layers in intestine: rate determinant of fatty acid absorption from micellar solutions. Science. 1971, 174: 1031-1033.
Kobayashi A, Ohbe Y, Yonekubo A: Fat absorption in patients with surgically repaired biliary atresia. Helv Paediatr Acta. 1983, 38: 307-314.
Minich DM, Kalivianakis M, Havinga R, Van Goor H, Stellaard F, Vonk RJ, Kuipers F, Verkade HJ: Bile diversion in rats leads to a decreased plasma concentration of linoleic acid which is not due to decreased net intestinal absorption of dietary linoleic acid. Biochim Biophys Acta. 1999, 1438: 111-119.
Ros E, Garcia-Puges A, Reixach M, Cuso E, Rodes J: Fat digestion and exocrine pancreatic function in primary biliary cirrhosis. Gastroenterology. 1984, 87: 180-187.
Narayanan VS, Storch J: Fatty acid transfer in taurodeoxycholate mixed micelles. Biochemistry. 1996, 35: 7466-7473. 10.1021/bi952979k.
Harries JT, Muller DP, McCollum JP, Lipson A, Roma E, Norman AP: Intestinal bile salts in cystic fibrosis: studies in the patient and experimental animal. Arch Dis Child. 1979, 54: 19-24.
Robb TA, Davidson GP, Kirubakaran C: Conjugated bile acids in serum and secretions in response to cholecystokinin/secretin stimulation in children with cystic fibrosis. Gut. 1985, 26: 1246-1256.
Weizman Z, Durie PR, Kopelman HR, Vesely SM, Forstner GG: Bile acid secretion in cystic fibrosis: evidence for a defect unrelated to fat malabsorption. Gut. 1986, 27: 1043-1048.
Roy CC, Weber AM, Morin CL, Lepage G, Brisson G, Yousef I, Lasalle R: Hepatobiliary disease in cystic fibrosis: a survey of current issues and concepts. J Pediatr Gastroenterol Nutr. 1982, 1: 469-478.
Knox R, Stein I, Levinson D, Tso P, Mansbach CM: Effect of fat pre-feeding on bile flow and composition in the rat. Biochim Biophys Acta. 1991, 1083: 65-70.
Connor WE, Witiak DT, Stone DB, Armstrong ML: Cholesterol balance and fecal neutral steroid and bile acid excretion in normal men fed dietary fats of different fatty acid composition. J Clin Invest. 1969, 48: 1363-1375.
Smit MJ, Temmerman AM, Wolters H, Kuipers F, Beynen AC, Vonk RJ: Dietary fish oil-induced changes in intrahepatic cholesterol transport and bile acid synthesis in rats. J Clin Invest. 1991, 88: 943-951.
Levy E: The 1991 Borden Award Lecture. Selected aspects of intraluminal and intracellular phases of intestinal fat absorption. Can J Physiol Pharmacol. 1992, 70: 413-419.
Levy E, Garofalo C, Rouleau T, Gavino V, Bendayan M: Impact of essential fatty acid deficiency on hepatic sterol metabolism in rats. Hepatology. 1996, 23: 848-857.
Ekelund K, Johansson C, Nylander B: Effects of 16,16 dimethyl prostaglandin E2 on food-stimulated pancreatic secretion and output of bile in man. Scand J Gastroenterol. 1977, 12: 457-460.
Cohen BI, Raicht RF, Mosbach EH: Sterol metabolism studies in the rat. Effects of primary bile acids (sodium taurochenodeoxycholate and sodium taurocholate) on sterol metabolism. J Lipid Res. 1977, 18: 223-231.
Gallo-Torres HE, Miller ON, Hamilton JG: Further studies on the role of bile salts in cholesterol esterification and absorption from the gut. Arch Biochem Biophys. 1971, 143: 22-36. 10.1016/0003-9861(71)90182-2.
Reynier MO, Montet JC, Gerolami A, Marteau C, Crotte C, Montet AM, Mathieu S: Comparative effects of cholic, chenodeoxycholic, and ursodeoxycholic acids on micellar solubilization and intestinal absorption of cholesterol. J Lipid Res. 1981, 22: 467-473.
Thompson GN: Excessive fecal taurine loss predisposes to taurine deficiency in cystic fibrosis. J Pediatr Gastroenterol Nutr. 1988, 7: 214-219.
De Curtis M, Santamaria F, Ercolini P, Vittoria L, De Ritis G, Garofalo V, Ciccimarra F: Effect of taurine supplementation on fat and energy absorption in cystic fibrosis. Arch Dis Child. 1992, 67: 1082-1085.
Merli M, Bertasi S, Servi R, Diamanti S, Martino F, De Santis A, Goffredo F, Quattrucci S, Antonelli M, Angelico M: Effect of a medium dose of ursodeoxycholic acid with or without taurine supplementation on the nutritional status of patients with cystic fibrosis: a randomized, placebo-controlled, crossover trial. J Pediatr Gastroenterol Nutr. 1994, 19: 198-203.
Smith LJ, Lacaille F, Lepage G, Ronco N, Lamarre A, Roy CC: Taurine decreases fecal fatty acid and sterol excretion in cystic fibrosis. A randomized double-blind trial. Am J Dis Child. 1991, 145: 1401-1404.
Thompson GN: Failure of taurine to improve fat absorption in cystic fibrosis. J Inherit Metab Dis. 1988, 11 Suppl 2: 158-160.
Belli DC, Levy E, Darling P, Leroy C, Lepage G, Giguere R, Roy CC: Taurine improves the absorption of a fat meal in patients with cystic fibrosis. Pediatrics. 1987, 80: 517-523.
Carrasco S, Codoceo R, Prieto G, Lama R, Polanco I: Effect of taurine supplements on growth, fat absorption and bile acid on cystic fibrosis. Acta Univ Carol [Med ] (Praha). 1990, 36: 152-156.
Colombo C, Setchell KD, Podda M, Crosignani A, Roda A, Curcio L, Ronchi M, Giunta A: Effects of ursodeoxycholic acid therapy for liver disease associated with cystic fibrosis. J Pediatr. 1990, 117: 482-489.
Sarfeh IJ, Beeler DA, Treble DH, Balint JA: Studies of the hepatic excretory defects in essential fatty acid deficiency. Their possible relationship to the genesis of cholesterol gallstones. J Clin Invest. 1974, 53: 423-430.
Trewhella MA, Collins FD: A comparison of the relative turnover of individual molecular species of phospholipids in normal rats and in rats deficient in essential fatty acids. Biochim Biophys Acta. 1973, 296: 34-50.
Lepage G, Paradis K, Lacaille F, Senechal L, Ronco N, Champagne J, Lenaerts C, Roy CC, Rasquin-Weber A: Ursodeoxycholic acid improves the hepatic metabolism of essential fatty acids and retinol in children with cystic fibrosis. J Pediatr. 1997, 130: 52-58.
Hofmann AF: The enterohepatic circulation of bile acids in man. Adv Intern Med. 1976, 21: 501-534.
Schreiber AJ, Simon FR: Overview of clinical aspects of bile salt physiology. J Pediatr Gastroenterol Nutr. 1983, 2: 337-345.
Goodchild MC, Murphy GM, Howell AM, Nutter SA, Anderson CM: Aspects of bile acid metabolism in cystic fibrosis. Arch Dis Child. 1975, 50: 769-778.
O'Brien S, Mulcahy H, Fenlon H, O'Broin A, Casey M, Burke A, FitzGerald MX, Hegarty JE: Intestinal bile acid malabsorption in cystic fibrosis. Gut. 1993, 34: 1137-1141.
Smalley CA, Brown GA, Parkes ME, Tease H, Brookes V, Anderson CM: Reduction of bile acid loss in cystic fibrosis by dietary means. Arch Dis Child. 1978, 53: 477-482.
Walters MP, Littlewood JM: Faecal bile acid and dietary residue excretion in cystic fibrosis: age group variations. J Pediatr Gastroenterol Nutr. 1998, 27: 296-300. 10.1097/00005176-199809000-00005.
Watkins JB, Tercyak AM, Szczepanik P, Klein PD: Bile salt kinetics in cystic fibrosis: influence of pancreatic enzyme replacement. Gastroenterology. 1977, 73: 1023-1028.
Vlahcevic ZR, Miller JR, Farrar JT, Swell L: Kinetics and pool size of primary bile acids in man. Gastroenterology. 1971, 61: 85-90.
Weber AM, Roy C, Lepage G, Chartrand L, Lasalle R: Interruption of the enterohepatic circulation of bile acids in cystic fibrosis. Gastroenterology. 1975, 68: 1066-
Jonas A, Diver-Haber A: Bile acid sequestration by the solid phase of stools in cystic fibrosis patients. Role of pancreatic enzymes. Dig Dis Sci. 1988, 33: 724-731. 10.1007/BF01540437.
Isenberg JN, Hendrix PY, Cox KL: Effect of short-term cimetidine administration on fecal bile acid losses in cystic fibrosis. J Pediatr Gastroenterol Nutr. 1983, 2: 447-451.
Lefebvre D, Ratelle S, Chartrand L, Roy CC: Reduced microbial transformation of bile acids in cystic fibrosis. Experientia. 1977, 33: 616-618.
de Rooij FW, van den Berg JW, Sinaasappel M, Bosman-Jacobs EP, Touw-Blommesteijn AC: Bile acid malabsorption in cystic fibrosis; membrane vesicles, a tool for revealing the role of the ileal brush border membrane. Acta Paediatr Scand Suppl. 1985, 317: 28-30.
Fondacaro JD, Heubi JE, Kellogg FW: Intestinal bile acid malabsorption in cystic fibrosis: a primary mucosal cell defect. Pediatr Res. 1982, 16: 494-498.
Stelzner M, Somasundaram S, Lee SP, Kuver R: Ileal mucosal bile acid absorption is increased in Cftr knockout mice. BMC Gastroenterol. 2001, 1: 10-10.1186/1471-230X-1-10.
Levy E, Goldstein R, Stankievicz H, Hager E, Freier S: Gastric handling of medium-chain triglycerides and subsequent metabolism in the suckling rat. J Pediatr Gastroenterol Nutr. 1984, 3: 784-789.
Symonds EL, Omari TI, Webster JM, Davidson GP, Butler RN: Relation between pancreatic lipase activity and gastric emptying rate in children with cystic fibrosis. J Pediatr. 2003, 143: 772-775. 10.1067/S0022-3476(03)00581-X.
Bali A, Stableforth DE, Asquith P: Prolonged small-intestinal transit time in cystic fibrosis. Br Med J (Clin Res Ed). 1983, 287: 1011-1013.
Dalzell AM, Freestone NS, Billington D, Heaf DP: Small intestinal permeability and orocaecal transit time in cystic fibrosis. Arch Dis Child. 1990, 65: 585-588.
Mack DR, Flick JA, Durie PR, Rosenstein BJ, Ellis LE, Perman JA: Correlation of intestinal lactulose permeability with exocrine pancreatic dysfunction. J Pediatr. 1992, 120: 696-701.
Seal S, McClean P, Walters M, Wolfe SP, Harding M, Coward W, Littlewood JM: Stable isotope studies of pancreatic enzyme release in vivo. Postgrad Med J. 1996, 72 Suppl 2: S37-S38.
Taylor CJ, Hillel PG, Ghosal S, Frier M, Senior S, Tindale WB, Read N: Gastric emptying and intestinal transit of pancreatic enzyme supplements in cystic fibrosis. Arch Dis Child. 1999, 80: 149-152.
Hjelte L, Melin T, Nilsson A, Strandvik B: Absorption and metabolism of [3H]arachidonic and [14C]linoleic acid in essential fatty acid-deficient rats. Am J Physiol. 1990, 259: G116-G124.
Snipes RL: Cellular dynamics in the jejunum of essential fatty acid deficient mice. Anat Rec. 1967, 159: 421-429. 10.1002/ar.1091590411.
FREYE HB, KURTZ SM, SPOCK A, CAPP MP: LIGHT AND ELECTRON MICROSCOPIC EXAMINATION OF THE SMALL BOWEL OF CHILDREN WITH CYSTIC FIBROSIS. J Pediatr. 1964, 64: 575-579.
Kent G, Oliver M, Foskett JK, Frndova H, Durie P, Forstner J, Forstner GG, Riordan JR, Percy D, Buchwald M: Phenotypic abnormalities in long-term surviving cystic fibrosis mice. Pediatr Res. 1996, 40: 233-241.
Cox KL, Isenberg JN, Ament ME: Gastric acid hypersecretion in cystic fibrosis. J Pediatr Gastroenterol Nutr. 1982, 1: 559-565.
Van Biervliet S, Eggermont E, Marien P, Hoffman I, Veereman G: Combined impact of mucosal damage and of cystic fibrosis on the small intestinal brush border enzyme activities. Acta Clin Belg. 2003, 58: 220-224.
Slomiany A, Liau YH, Carter SR, Newman LJ, Slomiany BL: Mucus glycoprotein fatty acyltransferase in patients with cystic fibrosis: effect on the glycoprotein viscosity. Biochem Biophys Res Commun. 1985, 132: 299-306. 10.1016/0006-291X(85)91022-8.
Schutt WH, Isles TE: Protein in meconium from meconium ileus. Arch Dis Child. 1968, 43: 178-181.
Wesley A, Forstner J, Qureshi R, Mantle M, Forstner G: Human intestinal mucin in cystic fibrosis. Pediatr Res. 1983, 17: 65-69.
Korotkova M, Strandvik B: Essential fatty acid deficiency affects the fatty acid composition of the rat small intestinal and colonic mucosa differently. Biochim Biophys Acta. 2000, 1487: 319-325.
Snipes RL: The effects of essential fatty acid deficiency on the ultrastructure and functional capacity of the jejunal epithelium. Lab Invest. 1968, 18: 179-189.
AAES-JORGENSEN E: Essential fatty acids. Physiol Rev. 1961, 41: 1-51.
Pandalai PK, Pilat MJ, Yamazaki K, Naik H, Pienta KJ: The effects of omega-3 and omega-6 fatty acids on in vitro prostate cancer growth. Anticancer Res. 1996, 16: 815-820.
Jiang WG, Eynard AR, Mansel RE: The pathology of essential fatty acid deficiency: is it cell adhesion mediated?. Med Hypotheses. 2000, 55: 257-262. 10.1054/mehy.1998.1191.
Juby LD, Rothwell J, Axon AT: Cellobiose/mannitol sugar test--a sensitive tubeless test for coeliac disease: results on 1010 unselected patients. Gut. 1989, 30: 476-480.
Hallberg K, Grzegorczyk A, Larson G, Strandvik B: Intestinal permeability in cystic fibrosis in relation to genotype. J Pediatr Gastroenterol Nutr. 1997, 25: 290-295. 10.1097/00005176-199709000-00008.
Gosden CM, Gosden JR: Fetal abnormalities in cystic fibrosis suggest a deficiency in proteolysis of cholecystokinin. Lancet. 1984, 2: 541-546. 10.1016/S0140-6736(84)90765-7.
Eynard AR, Monis B, Kalinec F, Leguizamon RO: Increased proliferation of the epithelium of the proximal alimentary tract of EFA-deficient rats: a light and electron microscopy study. Exp Mol Pathol. 1982, 36: 135-143. 10.1016/0014-4800(82)90088-0.
Thomson AB, Keelan M, Garg ML, Clandinin MT: Intestinal aspects of lipid absorption: in review. Can J Physiol Pharmacol. 1989, 67: 179-191.
Chow SL, Hollander D: A dual, concentration-dependent absorption mechanism of linoleic acid by rat jejunum in vitro. J Lipid Res. 1979, 20: 349-356.
Trotter PJ, Ho SY, Storch J: Fatty acid uptake by Caco-2 human intestinal cells. J Lipid Res. 1996, 37: 336-346.
Baier LJ, Bogardus C, Sacchettini JC: A polymorphism in the human intestinal fatty acid binding protein alters fatty acid transport across Caco-2 cells. J Biol Chem. 1996, 271: 10892-10896. 10.1074/jbc.271.20.11689.
Clarke SD, Armstrong MK: Cellular lipid binding proteins: expression, function, and nutritional regulation. FASEB J. 1989, 3: 2480-2487.
Ockner RK, Manning JA: Fatty acid-binding protein in small intestine. Identification, isolation, and evidence for its role in cellular fatty acid transport. J Clin Invest. 1974, 54: 326-338.
Sfeir Z, Ibrahimi A, Amri E, Grimaldi P, Abumrad N: Regulation of FAT/CD36 gene expression: further evidence in support of a role of the protein in fatty acid binding/transport. Prostaglandins Leukot Essent Fatty Acids. 1997, 57: 17-21. 10.1016/S0952-3278(97)90487-7.
Stahl A, Hirsch DJ, Gimeno RE, Punreddy S, Ge P, Watson N, Patel S, Kotler M, Raimondi A, Tartaglia LA, Lodish HF: Identification of the major intestinal fatty acid transport protein. Mol Cell. 1999, 4: 299-308. 10.1016/S1097-2765(00)80332-9.
Lobo MV, Huerta L, Ruiz-Velasco N, Teixeiro E, de la CP, Celdran A, Martin-Hidalgo A, Vega MA, Bragado R: Localization of the lipid receptors CD36 and CLA-1/SR-BI in the human gastrointestinal tract: towards the identification of receptors mediating the intestinal absorption of dietary lipids. J Histochem Cytochem. 2001, 49: 1253-1260.
Levy E, Menard D, Suc I, Delvin E, Marcil V, Brissette L, Thibault L, Bendayan M: Ontogeny, immunolocalisation, distribution and function of SR-BI in the human intestine. J Cell Sci. 2004, 117: 327-337. 10.1242/jcs.00856.
Berge KE, Tian H, Graf GA, Yu L, Grishin NV, Schultz J, Kwiterovich P, Shan B, Barnes R, Hobbs HH: Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science. 2000, 290: 1771-1775. 10.1126/science.290.5497.1771.
Lee MH, Lu K, Hazard S, Yu H, Shulenin S, Hidaka H, Kojima H, Allikmets R, Sakuma N, Pegoraro R, Srivastava AK, Salen G, Dean M, Patel SB: Identification of a gene, ABCG5, important in the regulation of dietary cholesterol absorption. Nat Genet. 2001, 27: 79-83. 10.1038/87170.
Repa JJ, Turley SD, Lobaccaro JA, Medina J, Li L, Lustig K, Shan B, Heyman RA, Dietschy JM, Mangelsdorf DJ: Regulation of absorption and ABC1-mediated efflux of cholesterol by RXR heterodimers. Science. 2000, 289: 1524-1529. 10.1126/science.289.5484.1524.
Mulligan JD, Flowers MT, Tebon A, Bitgood JJ, Wellington C, Hayden MR, Attie AD: ABCA1 is essential for efficient basolateral cholesterol efflux during the absorption of dietary cholesterol in chickens. J Biol Chem. 2003, 278: 13356-13366. 10.1074/jbc.M212377200.
Murthy S, Born E, Mathur SN, Field FJ: LXR/RXR activation enhances basolateral efflux of cholesterol in CaCo-2 cells. J Lipid Res. 2002, 43: 1054-1064. 10.1194/jlr.M100358-JLR200.
Iyer SP, Yao X, Crona JH, Hoos LM, Tetzloff G, Davis HRJ, Graziano MP, Altmann SW: Characterization of the putative native and recombinant rat sterol transporter Niemann-Pick C1 Like 1 (NPC1L1) protein. Biochim Biophys Acta. 2005
Klett EL, Patel SB: Biomedicine. Will the real cholesterol transporter please stand up. Science. 2004, 303: 1149-1150. 10.1126/science.1095519.
Briel M, Greger R, Kunzelmann K: Cl- transport by cystic fibrosis transmembrane conductance regulator (CFTR) contributes to the inhibition of epithelial Na+ channels (ENaCs) in Xenopus oocytes co-expressing CFTR and ENaC. J Physiol. 1998, 508 ( Pt 3): 825-836. 10.1111/j.1469-7793.1998.825bp.x.
Mall M, Bleich M, Kuehr J, Brandis M, Greger R, Kunzelmann K: CFTR-mediated inhibition of epithelial Na+ conductance in human colon is defective in cystic fibrosis. Am J Physiol. 1999, 277: G709-G716.
Xu Y, Clark JC, Aronow BJ, Dey CR, Liu C, Wooldridge JL, Whitsett JA: Transcriptional adaptation to cystic fibrosis transmembrane conductance regulator deficiency. J Biol Chem. 2003, 278: 7674-7682. 10.1074/jbc.M210277200.
McKenna MC, Hubbard VS, Bieri JG: Linoleic acid absorption from lipid supplements in patients with cystic fibrosis with pancreatic insufficiency and in control subjects. J Pediatr Gastroenterol Nutr. 1985, 4: 45-51.
Thompson GN: Relationships between essential fatty acid levels, pulmonary function and fat absorption in pre-adolescent cystic fibrosis children with good clinical scores. Eur J Pediatr. 1989, 148: 327-329. 10.1007/BF00444126.
Clark SB, Ekkers TE, Singh A, Balint JA, Holt PR, Rodgers JBJ: Fat absorption in essential fatty acid deficiency: a model experimental approach to studies of the mechanism of fat malabsorption of unknown etiology. J Lipid Res. 1973, 14: 581-588.
Kellner-Weibel G, Llera-Moya M, Connelly MA, Stoudt G, Christian AE, Haynes MP, Williams DL, Rothblat GH: Expression of scavenger receptor BI in COS-7 cells alters cholesterol content and distribution. Biochemistry. 2000, 39: 221-229. 10.1021/bi991666c.
Amri EZ, Bonino F, Ailhaud G, Abumrad NA, Grimaldi PA: Cloning of a protein that mediates transcriptional effects of fatty acids in preadipocytes. Homology to peroxisome proliferator-activated receptors. J Biol Chem. 1995, 270: 2367-2371. 10.1074/jbc.270.5.2367.
Murthy S, Born E, Mathur SN, Field FJ: Liver-X-receptor-mediated increase in ATP-binding cassette transporter A1 expression is attenuated by fatty acids in CaCo-2 cells: effect on cholesterol efflux to high-density lipoprotein. Biochem J. 2004, 377: 545-552.
Uehara Y, Engel T, Li Z, Goepfert C, Rust S, Zhou X, Langer C, Schachtrup C, Wiekowski J, Lorkowski S, Assmann G, von Eckardstein A: Polyunsaturated fatty acids and acetoacetate downregulate the expression of the ATP-binding cassette transporter A1. Diabetes. 2002, 51: 2922-2928.
Wang Y, Oram JF: Unsaturated fatty acids inhibit cholesterol efflux from macrophages by increasing degradation of ATP-binding cassette transporter A1. J Biol Chem. 2002, 277: 5692-5697. 10.1074/jbc.M109977200.
Heda GD, Marino CR: Surface expression of the cystic fibrosis transmembrane conductance regulator mutant DeltaF508 is markedly upregulated by combination treatment with sodium butyrate and low temperature. Biochem Biophys Res Commun. 2000, 271: 659-664. 10.1006/bbrc.2000.2684.
Marcil V, Delvin E, Seidman E, Poitras L, Zoltowska M, Garofalo C, Levy E: Modulation of lipid synthesis, apolipoprotein biogenesis, and lipoprotein assembly by butyrate. Am J Physiol Gastrointest Liver Physiol. 2002, 283: G340-G346.
Brown CR, Hong-Brown LQ, Biwersi J, Verkman AS, Welch WJ: Chemical chaperones correct the mutant phenotype of the delta F508 cystic fibrosis transmembrane conductance regulator protein. Cell Stress Chaperones. 1996, 1: 117-125. 10.1379/1466-1268(1996)001<0117:CCCTMP>2.3.CO;2.
Venglarik CJ, Bridges RJ, Frizzell RA: A simple assay for agonist-regulated Cl and K conductances in salt-secreting epithelial cells. Am J Physiol. 1990, 259: C358-C364.
Zhang XM, Wang XT, Yue H, Leung SW, Thibodeau PH, Thomas PJ, Guggino SE: Organic solutes rescue the functional defect in delta F508 cystic fibrosis transmembrane conductance regulator. J Biol Chem. 2003, 278: 51232-51242. 10.1074/jbc.M309076200.
Eidelman O, BarNoy S, Razin M, Zhang J, McPhie P, Lee G, Huang Z, Sorscher EJ, Pollard HB: Role for phospholipid interactions in the trafficking defect of Delta F508-CFTR. Biochemistry. 2002, 41: 11161-11170. 10.1021/bi020289s.
Arreaza-Plaza CA, Bosch V, Otayek MA: Lipid transport across the intestinal epithelial cell. Effect of colchicine. Biochim Biophys Acta. 1976, 431: 297-302.
Glickman RM, Perrotto JL, Kirsch K: Intestinal lipoprotein formation: effect of cholchicine. Gastroenterology. 1976, 70: 347-352.
Pavelka M, Gangl A: Effects of colchicine on the intestinal transport of endogenous lipid. Ultrastructural, biochemical, and radiochemical studies in fasting rats. Gastroenterology. 1983, 84: 544-555.
Chun J, Auer KA, Jacobson BS: Arachidonate initiated protein kinase C activation regulates HeLa cell spreading on a gelatin substrate by inducing F-actin formation and exocytotic upregulation of beta 1 integrin. J Cell Physiol. 1997, 173: 361-370. 10.1002/(SICI)1097-4652(199712)173:3<361::AID-JCP8>3.0.CO;2-L.
Jiang WG, Bryce RP, Horrobin DF, Mansel RE: Regulation of tight junction permeability and occludin expression by polyunsaturated fatty acids. Biochem Biophys Res Commun. 1998, 244: 414-420. 10.1006/bbrc.1998.8288.
Anant S, Davidson NO: Molecular mechanisms of apolipoprotein B mRNA editing. Curr Opin Lipidol. 2001, 12: 159-165. 10.1097/00041433-200104000-00009.
Le Beyec J, Chauffeton V, Kan HY, Janvier PL, Cywiner-Golenzer C, Chatelet FP, Kalopissis AD, Zannis V, Chambaz J, Pincon-Raymond M, Cardot P: The -700/-310 fragment of the apolipoprotein A-IV gene combined with the -890/-500 apolipoprotein C-III enhancer is sufficient to direct a pattern of gene expression similar to that for the endogenous apolipoprotein A-IV gene. J Biol Chem. 1999, 274: 4954-4961. 10.1074/jbc.274.8.4954.
Hussain MM, Kancha RK, Zhou Z, Luchoomun J, Zu H, Bakillah A: Chylomicron assembly and catabolism: role of apolipoproteins and receptors. Biochim Biophys Acta. 1996, 1300: 151-170.
Wetterau JR, Aggerbeck LP, Bouma ME, Eisenberg C, Munck A, Hermier M, Schmitz J, Gay G, Rader DJ, Gregg RE: Absence of microsomal triglyceride transfer protein in individuals with abetalipoproteinemia. Science. 1992, 258: 999-1001.
Jones B, Jones EL, Bonney SA, Patel HN, Mensenkamp AR, Eichenbaum-Voline S, Rudling M, Myrdal U, Annesi G, Naik S, Meadows N, Quattrone A, Islam SA, Naoumova RP, Angelin B, Infante R, Levy E, Roy CC, Freemont PS, Scott J, Shoulders CC: Mutations in a Sar1 GTPase of COPII vesicles are associated with lipid absorption disorders. Nat Genet. 2003, 34: 29-31. 10.1038/ng1145.
Mansbach CM, Nevin P: Intracellular movement of triacylglycerols in the intestine. J Lipid Res. 1998, 39: 963-968.
Levy E, Thibault L, Garofalo C, Messier M, Lepage G, Ronco N, Roy CC: Combined (n-3 and n-6) essential fatty deficiency is a potent modulator of plasma lipids, lipoprotein composition, and lipolytic enzymes. J Lipid Res. 1990, 31: 2009-2017.
Bubien JK: CFTR may play a role in regulated secretion by lymphocytes: a new hypothesis for the pathophysiology of cystic fibrosis. Pflugers Arch. 2001, 443 Suppl 1: S36-S39. 10.1007/s004240100641.
Moss RB, Hsu YP, Olds L: Cytokine dysregulation in activated cystic fibrosis (CF) peripheral lymphocytes. Clin Exp Immunol. 2000, 120: 518-525. 10.1046/j.1365-2249.2000.01232.x.
Pan J, Bear C, Farragher S, Cutz E, Yeger H: Cystic fibrosis transmembrane conductance regulator modulates neurosecretory function in pulmonary neuroendocrine cell-related tumor cell line models. Am J Respir Cell Mol Biol. 2002, 27: 553-560.
Biwersi J, Emans N, Verkman AS: Cystic fibrosis transmembrane conductance regulator activation stimulates endosome fusion in vivo. Proc Natl Acad Sci U S A. 1996, 93: 12484-12489. 10.1073/pnas.93.22.12484.
Asp L, Claesson C, Boren J, Olofsson SO: ADP-ribosylation factor 1 and its activation of phospholipase D are important for the assembly of very low density lipoproteins. J Biol Chem. 2000, 275: 26285-26292. 10.1074/jbc.M003520200.
Gusarova V, Brodsky JL, Fisher EA: Apolipoprotein B100 exit from the endoplasmic reticulum (ER) is COPII-dependent, and its lipidation to very low density lipoprotein occurs post-ER. J Biol Chem. 2003, 278: 48051-48058. 10.1074/jbc.M306898200.
Yoo JS, Moyer BD, Bannykh S, Yoo HM, Riordan JR, Balch WE: Non-conventional trafficking of the cystic fibrosis transmembrane conductance regulator through the early secretory pathway. J Biol Chem. 2002, 277: 11401-11409. 10.1074/jbc.M110263200.
Fu L, Sztul E: Traffic-independent function of the Sar1p/COPII machinery in proteasomal sorting of the cystic fibrosis transmembrane conductance regulator. J Cell Biol. 2003, 160: 157-163. 10.1083/jcb.200210086.
Becker W, Mansson JE: Incorporation of 14C into tissue lipids after oral administration of [1-14C]linoleic acid in rats fed different levels of essential fatty acids. J Nutr. 1985, 115: 1248-1258.
Williams MA, Tinoco J, Yang YT, Bird MI, Hincenbergs I: Feeding pure docosahexaenoate or arachidonate decreases plasma triacylglycerol secretion in rats. Lipids. 1989, 24: 753-758.
Coleman RA, Wang P, Bhat BG: Diradylglycerols alter fatty acid inhibition of monoacylglycerol acyltransferase activity in Triton X-100 mixed micelles. Biochemistry. 1998, 37: 5916-5922. 10.1021/bi9802972.
Chautan M, Charbonnier M, Leonardi J, Andre M, Lafont H, Nalbone G: Modulation of lipid chylomicron-synthesizing enzymes in rats by the dietary (n-6):(n-3) fatty acid ratio. J Nutr. 1991, 121: 1305-1310.
Stan S, Delvin EE, Seidman E, Rouleau T, Steinmetz A, Bendayan M, Yotov W, Levy E: Modulation of apo A-IV transcript levels and synthesis by n-3, n-6, and n-9 fatty acids in CACO-2 cells. J Cell Biochem. 1999, 75: 73-81. 10.1002/(SICI)1097-4644(19991001)75:1<73::AID-JCB8>3.0.CO;2-K.
Wang H, Lu S, Du J, Yao Y, Berschneider HM, Black DD: Regulation of apolipoprotein secretion by long-chain polyunsaturated fatty acids in newborn swine enterocytes. Am J Physiol Gastrointest Liver Physiol. 2001, 280: G1137-G1144.
Murthy S, Albright E, Mathur SN, Davidson NO, Field FJ: Apolipoprotein B mRNA abundance is decreased by eicosapentaenoic acid in CaCo-2 cells. Effect on the synthesis and secretion of apolipoprotein B. Arterioscler Thromb. 1992, 12: 691-700.
Kratz M, Wahrburg U, von Eckardstein A, Ezeh B, Assmann G, Kronenberg F: Dietary mono- and polyunsaturated fatty acids similarly increase plasma apolipoprotein A-IV concentrations in healthy men and women. J Nutr. 2003, 133: 1821-1825.
Yao Y, Eshun JK, Lu S, Berschneider HM, Black DD: Regulation of triacylglycerol and phospholipid trafficking by fatty acids in newborn swine enterocytes. Am J Physiol Gastrointest Liver Physiol. 2002, 282: G817-G824.
Jiang WG, Bryce RP, Horrobin DF, Mansel RE: gamma-Linolenic acid blocks cell cycle progression by regulating phosphorylation of p27kip1 and p57kip2 and their interactions with other cycle regulators in cancer cells. Int J Oncol. 1998, 13: 611-617.
All the authors have contributed to the preparation of this review. The authors thank Schohraya Spahis for her expert technical assistance. This paper was supported by research grants from the Canadian Institutes of Health Research (CIHR) (MT 10584 and MOP 49433)
The author(s) declare that they have no competing interests.
Authors’ original submitted files for images
Below are the links to the authors’ original submitted files for images.
About this article
Cite this article
Peretti, N., Marcil, V., Drouin, E. et al. Mechanisms of lipid malabsorption in Cystic Fibrosis: the impact of essential fatty acids deficiency. Nutr Metab (Lond) 2, 11 (2005). https://doi.org/10.1186/1743-7075-2-11
- Cystic Fibrosis
- Cystic Fibrosis Transmembrane Conductance Regulator
- Cystic Fibrosis Patient
- Pancreatic Lipase