The cholesterol absorption inhibitor ezetimibe can significantly reduce plasma cholesterol concentrations by inhibiting the Niemann-Pick C1-like 1 protein (NPC1L1), an intestinal sterol influx transporter that can actively facilitate the uptake of cholesterol for intestinal absorption. Unexpectedly, ezetimibe treatment also induces a complete resistance to cholesterol gallstone formation and nonalcoholic fatty liver disease (NAFLD) in addition to preventing hypercholesterolemia in mice on a Western diet. Because chylomicrons are the vehicles with which the enterocytes transport cholesterol and fatty acids into the body, ezetimibe could prevent these two most prevalent hepatobiliary diseases possibly through the regulation of chylomicron-derived cholesterol and fatty acid metabolism in the liver. It is highly likely that there is an intestinal and hepatic cross-talk through the chylomicron pathway. Therefore, understanding the molecular mechanisms whereby cholesterol and fatty acids are absorbed from the intestine could offer an efficacious novel approach to the prevention and the treatment of cholesterol gallstones and NAFLD. 1. Introduction The small intestine is a unique organ providing dietary and reabsorbed biliary cholesterol to the body [1–3]. High plasma total and low-density lipoprotein (LDL) cholesterol concentrations are an important risk factor for cardiovascular diseases. The restriction of dietary calories, cholesterol, and saturated fat has been used as the primary initial therapeutic modality for the treatment of patients with dyslipidemia [4]. However, the reduction of dietary cholesterol is frequently not associated with a significant decrease in circulating LDL cholesterol levels, despite significant restrictions in dietary intake. Therefore, pharmacological intervention aimed to reduce intestinal cholesterol absorption is potentially an effective way of lowering plasma total and LDL cholesterol concentrations [2]. The use of cholesterol absorption inhibitors for treating hypercholesterolemia has a long history, and several classes of compounds such as hydrophilic bile acid ursodeoxycholic acid (UDCA) [2], the bile acid sequestrants, specific lipase inhibitors, the intestinal acyl-CoA:cholesterol acyltransferase (ACAT) inhibitors [5, 6], and cholesterol ester transfer protein inhibitors [7] have been developed, and some of them are currently being evaluated in clinical trials. Recently, the discovery and development of ezetimibe, a novel, selective, and potent inhibitor that effectively blocks intestinal absorption of dietary and
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