Influence of class B scavenger receptors on cholesterol flux across the brush border membrane and intestinal absorption

Abstract

The effi ciency of absorption of dietary cholesterol in the small intestine affects plasma LDL cholesterol levels and thereby cardiovascular disease risk ( 1, 2 ). Consequently, there is great interest in understanding the mechanism of intestinal cholesterol absorption and inhibiting the process to reduce plasma cholesterol levels. Ezetimibe is such an inhibitor whose target is the protein NiemannPick C1-like 1 (NPC1L1) ( 3, 4 ); the importance of this protein in cholesterol absorption is refl ected by the fact that the absorption effi ciency is greatly reduced in mice lacking the gene encoding NPC1L1 ( 5, 6 ). Experiments with knockout and transgenic mice have variously demonstrated that acylCoA:cholesterol-acyltransferase-2 (ACAT-2) ( 7-9 ) and ATP binding cassette half transporters G5 and G8 (ABCG5/G8) ( 10-13 ) also play critical roles in the cholesterol absorption pathway. The above proteins are all involved in enterocyte cholesterol homeostasis ( 14, 15 ), but factors such as lipase activity and bile salt availability in the earlier digestive phase of the pathway are also critical (for recent reviews, see Refs. 14 and 16 ). Current understanding of the proteins and mechanisms controlling the uptake of cholesterol from the lumen of the small intestine into and across the brush border membrane (BBM) is relatively limited. Here, we distinguish between cholesterol uptake and cholesterol absorption, defi ning the former as the process of cholesterol transfer from the donor particle in the lumen of the small intestine to the BBM and the latter as the cascade of transport steps Press, May 19, 2009 DOI 10.1194 Abbreviations: ABCG5/G8, ATP binding cassette half transporters G5 and G8; ACAT-2, acylCoA:cholesterol-acyltransferase-2; BBM, brush border membrane; BBMV, brush border membrane vesicle; BSM, mixed bile salt micelle; CD36, cluster determinant 36; HFHC, high-fat/ high-cholesterol diet; NPC1L1, Niemann Pick C1-Like 1; SR-BI, scavenger receptor class B, type 1; SUV, small unilamellar vesicle; WT, wild type. Published, JLR Papers in

Intestinal SR-BI does not impact cholesterol absorption or transintestinal cholesterol efflux in mice

“…There is strong support for SR-BI binding cholesterol in isolated BBMVs ( 55,56 ). However, binding of cholesterol to BBMV is not predictive of intestinal cholesterol absorption rates in mice ( 70 ). These studies strongly suggest that ex vivo binding of cholesterol to BBMV does not accurately predict the true rate of intestinal cholesterol absorption, and results using the BBMV system need to be validated using standard in vivo assays for cholesterol absorption such as the fecal dual-isotope assay or lymph duct cannulations.…”

Intestinal CREBH overexpression prevents high-cholesterol diet-induced hypercholesterolemia by reducing Npc1l1 expression

“…Intestinal ABCA1 deficiency leads to deficient HDL biogenesis, thereby reducing cholesterol influx into the circulation [29], [30]. SRB1 is involved in the production of intestinal chylomicrons [41], which mediate the uptake of cholesterol from the lumen of the proximal small intestine [42], [43]. Reduced expression of these genes in small intestine of CREBH Tg mice likely also contributes to the reduced absorption and elevated excretion of cholesterol.…”

Transporters for the Intestinal Absorption of Cholesterol, Vitamin E, and Vitamin K

“…However, fecal lipid analyses showed that there were no significant differences in the intestinal absorption of fatty acids and cholesterol between WT and CD36 KO mice 12, 13) . This result suggests that CD36 in the small intestine is unlikely to be involved in the apical uptake of these lipids.…”