Ezetimibe: Its Novel Effects on the Prevention and the Treatment of Cholesterol Gallstones and Nonalcoholic Fatty Liver Disease

Figure 1

Within the intestinal lumen, the micellar solubilization of sterols facilitates movement through the diffusion barrier overlying the surface of the absorptive cells. In the presence of bile acids, large amounts of the sterol molecules are delivered to the aqueous-membrane interface so that their uptake rate is greatly increased. The Niemann-Pick C1-like 1 protein (NPC1L1), a newly identified sterol influx transporter, is located at the apical membrane of the enterocyte and may actively facilitate the uptake of cholesterol and plant sterols by promoting the passage of these molecules across the brush border membrane of the enterocyte. In contrast, ABCG5/G8 promote active efflux of cholesterol and plant sterols from the enterocyte into the intestinal lumen for excretion. The combined regulatory effects of NPC1L1 and ABCG5/G8 play a critical role in modulating the amount of cholesterol that reaches the lymph from the intestinal lumen. Ezetimibe may reduce cholesterol uptake by the enterocytes through the NPC1L1 pathway, possibly a transporter-facilitated mechanism. Absorbed cholesterol as well as some that is newly synthesized from acetate by 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) within the enterocyte is esterified by acyl-CoA:cholesterol acyltransferase isoform 2 (ACAT2) to form cholesteryl esters. It is likely that fatty acids (FA) and monoacylglycerol (MG) could be taken up into enterocytes by facilitated transport. With the assistance of fatty acid binding protein 4 (FABP4), fatty acids and monoacylglycerol are transported into the smooth endoplasmic reticulum (SER) where they are used for the synthesis of diacylglycerol (DG) and then triacylglycerol (TG). Glucose is transported into the SER for the synthesis of phospholipids (PL) through the phosphatidic acid (PA) pathway (abbreviation: α-GP, α-glycerophosphate). All of these lipids participate in the formation of chylomicrons, a process which also requires the synthesis of apolipoprotein (APO)-B48 and the activity of microsomal triglyceride transfer protein (MTTP). As observed in lymph, the core of the secreted chylomicrons contains triglycerides and cholesteryl esters and the surface of the particles is a monolayer containing phospholipids, mainly phosphatidylcholine, unesterified cholesterol and apolipoproteins including APO-B48, APO-AI, and APO-AIV. Therefore, intestinal cholesterol absorption is a multistep process that is regulated by multiple genes. Reproduced with modifications and with permission from [50].