Fig. 3

Regulation of cholesterol transport. Daily food and the hepatic endogenous synthesis are the two main sources of human cholesterol, of which dietary free cholesterol (FC) uptake is mediated by Niemann-Pick C1 Like 1 (NPC1L1) protein in enterocytes. The endocytosis of cholesterol by NPC1L1 responds to the change of cellular cholesterol concentration. FC taken up by NPC1L1 in enterocytes is esterified to cholesteryl ester (CE) by acyl-CoA:cholesterol acyltransferase 2 (ACAT2), which is loaded into ApoB-48 with triglycerides (TG) mediated by microsomal triglyceride transfer protein (MTP), to form chylomicron (CM). After TG in CM is hydrolyzed and utilized, most of the remaining cholesterol will be absorbed through low-density lipoprotein receptor (LDLR) in the liver. In contrast, some unesterified cholesterol is pumped back to the intestinal lumen by ATP-binding cassette (ABC) transport proteins G5 and G8 (ABCG5/ABCG8) or synthesized into pre-β-HDL by ABCA1 and released into circulation. Cholesterol synthesized endogenously in the liver is converted into VLDL with TG, ApoB-100, and most of VLDL is then converted into LDL, which is the main carrier for transporting endogenous cholesterol. LDL is taken up by scavenger receptors in macrophages, where expression of CD36, scavenger receptor A1 (SR-A1), and LDL receptor 1 (LOX1) is increased in atherosclerosis, further promoting cholesterol accumulation. LDL is endocytosed into macrophages and hydrolyzed by lipase (LAL) to produce FC. Excess FC is esterified by ACAT1 and stored as lipid droplets, and the excess accumulation of CE in macrophages can contribute to formation of foam cells. To mediate cholesterol efflux, macrophages hydrolyze CE into FC by the neutral cholesteryl ester hydrolase (NEH). Macrophage-mediated cholesterol efflux includes simple diffusion, SR-BI-facilitated diffusion, and ABCA1/ABCG1-mediated efflux. Among them, simple diffusion dominates cholesterol efflux in normal macrophages, regulated by cholesterol concentrations. In cholesterol overloaded macrophages, ABCA1 and ABCG1 are critical for cholesterol efflux. ABCA1 is able to bind to ApoA-I to mediate the production of pre-β-HDL, lecithin cholesterol acyltransferase (LCAT) further matures pre-β-HDL particles into HDL3, while ABCG1 and SR-BI mediate cholesterol flow directly to HDL3. HDL3 is further esterified by LCAT to produce HDL2, in which CE is eventually taken up by SR-BI in the liver and converted to FC. In addition, CE in HDL2 particles can be exchanged by cholesteryl ester transfer protein (CETP) to LDL particles, which are subsequently taken up by LDLR. Excess cholesterol in the liver is excreted into the bile mediated by ABCG5/ABCG8 and eventually enters the intestinal lumen for excretion in feces. Some other cholesterol in the blood can be excreted directly into the intestinal lumen via transintestinal cholesterol excretion (TICE) pathway in enterocytes