Opposing Gatekeepers of Apical Sterol Transport: Niemann-Pick C1-Like 1 (NPC1L1) and ATP-Binding Cassette Transporters G5 and G8 (ABCG5/ABCG8)

Abstract

Cholesterol is essential for the growth and function of all mammalian cells, but abnormally elevated levels of circulating low-density lipoprotein cholesterol (LDL-C) are a major risk factor for the development of atherosclerotic cardiovascular disease (ASCVD). For many years, statin drugs have been used to effectively lower LDL-C, but ASCVD still persists in most of the world. Hence, additional LDL-C lowering is now recommended, and the search for therapeutic strategies that work in synergy with statins has now begun. Intestinal absorption and biliary excretion of cholesterol represent two major pathways and continue to show promise as druggable processes. Importantly, both of these complex physiological pathways are tightly regulated by key proteins located at the apical surface of the small intestine and the liver. One of these proteins, the target of ezetimibe Niemann-Pick C1-Like 1 (NPC1L1), was recently identified to be essential for intestinal cholesterol absorption and protect against excessive biliary sterol loss. In direct opposition of NPC1L1, the heterodimer of ATP-binding cassette transporters G5 and G8 (ABCG5/ABCG8) has been shown to be critical for promoting biliary cholesterol secretion in the liver, and has also been proposed to play a direct role in intestinal disposal of sterols. The purpose of this review is to summarize the current state of knowledge regarding the function of these opposing apical cholesterol transporters, and provide a framework for future studies examining these proteins.

Fig. 1

Role of NPC1L1 and ABCG5/ABCG8 in enterohepatic circulation of sterols. In the gut lumen, free cholesterol (FC) derived from diet and bile is mixed with bile acids (BA) and phospholipids (PL) to form micelles. FC in micelles is transported by NPC1L1 into the absorptive enterocyte where the majority of FC is converted to cholesteryl ester (CE) for the assembly into chylomicrons (Chylo.) for delivery into the body. A proportion of FC in enterocyte is presumably secreted back into the gut lumen by ABCG5/ABCG8. Chylomicrons deliver their cargo (FC and CE) to the liver. In hepatocytes, a proportion of FC is secreted into the canalicular bile by ABCG5/ABCG8. FC in the canalicular bile may be recaptured by NPC1L1 back into hepatocyte or delivered to the gut lumen for another round of enterohepatic circulation. Importantly, ezetimibe (EZ) blocks NPC1L1-dependent sterol uptake at both the apical surface of enterocytes and the canalicular membrane of hepatocytes.