FIGURE 1.

Pharmacologic approaches to lower LDL cholesterol. Statins inhibit the rate-limiting enzyme of cholesterol biosynthesis, HMG-CoA reductase, leading to decreased hepatic cholesterol production. Ezetimibe is an inhibitor of NPC1L1 which facilitates absorption of intestinal cholesterol and therefore selectively decreases dietary cholesterol uptake and hepatic cholesterol supply. The inhibition of cholesterol synthesis or intestinal absorption both lead to an upregulation of the LDL receptor and subsequently, enhance LDL uptake and lower LDL cholesterol serum concentrations. Therapeutic inhibition of PCSK9 also leads to a higher density of LDL receptors on the hepatocyte surface, but not primarily through targeting cholesterol metabolism, but by affecting LDL receptor degradation and recycling pathways (Figure 2). HMG-CoA, 3-hydroxy-3-methylglutaryl-coenzyme A; LDL, low-density lipoprotein; PCSK9, proprotein convertase subtilisin/kexin type 9; NPC1L1, Niemann-Pick C1-like protein 1.