Hepatic cholesterol and bile acid metabolism and intestinal cholesterol absorption in scavenger receptor class B type I-deficient mice

Abstract

The scavenger receptor class B type I (SR-BI), which is expressed in the liver and intestine, plays a critical role in cholesterol metabolism in rodents. While hepatic SR-BI expression controls high density lipoprotein (HDL) cholesterol metabolism, intestinal SR-BI has been proposed to facilitate cholesterol absorption. To evaluate further the relevance of SR-BI in the enterohepatic circulation of cholesterol and bile salts, we studied biliary lipid secretion, hepatic sterol content and synthesis, bile acid metabolism, fecal neutral sterol excretion, and intestinal cholesterol absorption in SR-BI knockout mice. SR-BI deficiency selectively impaired biliary cholesterol secretion, without concomitant changes in either biliary bile acid or phospholipid secretion. Hepatic total and unesterified cholesterol contents were slightly increased in SR-BI-deficient mice, while sterol synthesis was not significantly changed. Bile acid pool size and composition, as well as fecal bile acid excretion, were not altered in SR-BI knockout mice. Intestinal cholesterol absorption was somewhat increased and fecal sterol excretion was slightly decreased in SR-BI knockout mice relative to controls. These findings establish the critical role of hepatic SR-BI expression in selectively controlling the utilization of HDL cholesterol for biliary secretion. In contrast, SR-BI expression is not essential for intestinal cholesterol absorption. -Mardones, P.

Berberrubine and its analog, hydroxypropyl‐berberrubine, regulate LDLR and PCSK9 expression via the ERK signal pathway to exert cholesterol‐lowering effects in human hepatoma HepG2 cells

“…Moreover, the LDLR pathway is the main route of hepatocellular cholesterol metabolism, and the expression of LDLR reflects the content of cellular cholesterol. 47 Consistent with the effects of BBR, M3, and A8 on LDLR expression, these 3 compounds could significantly reduce the cholesterol content in HepG2 cells, while M3 and A8 showed better potential effects on cholesterol lowering than BBR. When compared with the effect of several statins (for example atorvastatin, lovastatin, and simvastatin), 48,49 M3 and A8 exhibited similar decrease (30%-40%) on cellular cholesterol content in HepG2 cells.…”

Localization of the Lipid Receptors CD36 and CLA-1/SR-BI in the Human Gastrointestinal Tract: Towards the Identification of Receptors Mediating the Intestinal Absorption of Dietary Lipids

“…Simultaneous expression of CD36 and CLA-1/SR-BI in the proximal intestine might serve either to guarantee, by acting redundantly, a vital function and/or to allow a fine-tuned modulation of lipid absorption. Interestingly, it has recently been reported that in SR-BI deficient mice, intestinal cholesterol absorption is normal, suggesting the necessity of other molecules able to compensate for the loss of intestinal absorptive activity (Mardones et al 2001). Selective expression of CD36 in the proximal intestine is consistent with the observed regional expression of intestinal genes involved in the absorption of nutrients (lipids and non-lipids) in the diet (Shaw-Smith and Walters 1997).…”

Insulin increases cholesterol uptake, lipid droplet content, and apolipoprotein B secretion in CaCo‐2 cells by upregulating SR‐BI via a PI3K, AKT, and mTOR‐dependent pathway

“…The role of intestinal SR-BI on cholesterol absorption remains controversial. Studies showing either no effect of SR-BI germline deletion on intestinal cholesterol absorption in mice 15 or minor effects of increasing/knocking down SR-BI levels in CaCo-2 cells 27 and animal models 17 sharply contrast with studies showing high-affinity cholesterol binding in CaCo-2 cells 28 and increased cholesterol absorption after moderate intestinal SR-BI overexpression. 16,29 Herein, we show that, in polarized CaCo-2 cells, SR-BI-cholesterol binding activity is required for insulininduced intracellular lipid accumulation, cholesterol uptake, and apo B-containing lipoprotein secretion, suggesting that SR-BI may be involved in triglyceride rather than cholesterol intestinal absorption.…”

“…In mice, SR-BI gene deletion has no apparent effect on intestinal cholesterol absorption. 15 On the contrary, modest transgenic overexpression of SR-BI in enterocytes has been reported to increase cholesterol and triglyceride absorption rates in mice. 16 Nonetheless, these results failed to be replicated in a more recent study.…”