Fig. 2

Statins inhibit synthesis of cholesterol and MK-4. (a) The synthesis of cholesterol begins with the conversion of acetyl-CoA, a substance formed through the breakdown of glucose or fatty acids within the mitochondria, into 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) in the cytoplasm. This conversion is catalyzed by the enzyme HMG-CoA synthase. HMG-CoA reductase then converts HMG-CoA into mevalonate, which is further modified into farnesyl pyrophosphate (FPP). FPP undergoes cyclization steps to synthesize squalene, which is later converted into lanosterol. FPP can also be transformed into GGPP, a precursor for MK-4 synthesis. UBIAD1 plays a major role in this process as it facilitates the conversion of GGPP into MK-4. (b) By inhibiting the HMG-CoA reductase enzyme, statins reduce the levels of mevalonic acid, a precursor for cholesterol and isoprenoids, including GGPP. Since UBIAD1 uses GGPP as a substrate for vitamin K2 (MK-4) biosynthesis, the use of statins may indirectly decrease GGPP production, thereby affecting the availability of MK-4. However, despite the excessive abundance of GGPP, the levels of generated MK-4 were not fully restored, suggesting the likely direct inhibition of UBIAD1-mediated MK-4 synthetase activity by statins