Role of MTP in cellular cholesterol ester biosynthesis. (A) ACAT, a membrane integral enzyme is shown (yellow arrows) to convert free cholesterol present in the endoplasmic reticulum (ER) leaflets into cholesterol esters that remain within the membrane bilayer. MTP is shown to transfer both free cholesterol and cholesterol esters from the ER membranes to apoB-lipoproteins in the ER lumen. It should be pointed out that MTP could transfer both free and esterified cholesterol to apoB that is still associated with membranes. The thickness of orange arrows is meant to show that MTP most likely prefers cholesteryl esters over free cholesterol for transfer. (B) In MTP deficient conditions, transfer of free and esterified cholesterol to apoB-lipoproteins is reduced. Initially this might lead to accumulation of cholesteryl esters. When a high enough concentration of cholesteryl esters is achieved then ACAT activity is inhibited due to product inhibition leading to accumulation of free cholesterol. (C) In the absence of ACAT activity, it is anticipated that cells accumulate more free cholesterol. Indeed, this is known to happen in cells that do not secrete apoB-lipoproteins, such as macrophages. However, in cells that are able to synthesize apoB-containing lipoproteins, MTP can transfer free cholesterol to lipoproteins avoiding excess free cholesterol accumulation in the ER membrane.