Hepatic Scavenger Receptor BI Promotes Rapid Clearance of High Density Lipoprotein Free Cholesterol and Its Transport into Bile

Abstract

The clearance of free cholesterol from plasma lipoproteins by tissues is of major quantitative importance, but it is not known whether this is passive or receptormediated. Based Plasma high density lipoprotein (HDL)1 plays a key role in maintaining cholesterol homeostasis. Epidemiological studies demonstrated a strong inverse correlation between HDL levels and the risk of coronary artery disease (1). Although detailed mechanisms remain uncertain, it has been proposed that HDL promotes reverse cholesterol transport by facilitating transfer of cholesterol from peripheral tissues to the liver for secretion into bile (Ref. 2; see Ref. 3 for a recent review). Early studies using HDL and low density lipoprotein (LDL) with radiolabeled free cholesterol (FC) showed that FC in HDL is the preferred source for biliary cholesterol (4 -8). Recent work with plant sterols provided further evidence that HDL is the preferred carrier for the transport of cholesterol into bile (9). Based on the observations that HDL FC is preferentially utilized for biliary secretion and that, in tissue culture studies, HDL, but not LDL, selectively binds FC (10), Schwartz et al. (5) predicted that a cell-surface HDL receptor might be involved in the hepatic uptake of HDL FC. As a counterpoint to this idea, free cholesterol exchanges readily between lipoproteins and cells, suggesting that passive FC uptake by the liver might be possible.Scavenger receptor BI (SR-BI) has recently been identified as an authentic HDL receptor that mediates the selective uptake of HDL cholesteryl ester (CE) (11) and bi-directional transfer of FC between HDL and cells (12, 13). Its tissue distribution (11,14) and regulatable expression in the adrenal gland, testis, and ovary (14, 15) indicate that the receptor plays an important physiological role in cholesterol metabolism (16,17). Hepatic overexpression of SR-BI leads to decreased HDL levels in mice (18 -20) due to accelerated hepatic uptake of HDL CE and subsequently increased HDL CE and protein catabolism (19). On the other hand, decreased expression of SR-BI in gene-targeted mice results in increased HDL levels (21, 22). Furthermore, SR-BI mRNA is expressed in thickened intima of atheromatous aorta (12), and the receptor suppresses the development of atherosclerosis in SR-BI transgenic (SR-BI Tg)/LDL receptor-deficient compound mice fed the Paigen diet (23).In our previous work, we found that, in transfected Chinese hamster ovary cells, SR-BI mediates the cellular uptake of HDL FC as well as CE (12). Moreover, SR-BI promotes cholesterol efflux from cells to HDL (12, 13) or protein-free phospholipid (PL) vesicles (13), and the efflux rates correlate with the expression level of SR-BI in different cell lines (Refs. 12 and 13; see Ref. 24 for review). In mice with hepatic overexpression of SR-BI, the biliary concentration of cholesterol is increased (18,25). These results led us to hypothesize that SR-BI plays a physiological role in vivo in promoting the hepatic uptake of HDL FC and facilitating the secretion of...

Scavenger Receptor Class B Type I Mediates Biliary Cholesterol Secretion Independent of ATP-Binding Cassette Transporter g5/g8 in Mice†

“…SR-BI knockout mice show a 45% decrease in biliary cholesterol secretion rates, 16 whereas SR-BI overexpression increases biliary cholesterol content. 8,9,25 However, thus far the obligate heterodimeric ATP-binding cassette transporters Abcg5/Abcg8 have been characterized to represent the major and supposedly ratecontrolling transport system for cholesterol excretion into bile. The role of Abcg5/Abcg8 has been substantiated by showing that overexpression of these transporters results in increased biliary cholesterol secretion 19 and that knockouts for Abcg5 or Abcg8 have a decrease in biliary cholesterol secretion rates by about 75%.…”

“…[3][4][5][6] In hepatocytes, which is a highly polarized cell type, SR-BI is the main receptor responsible for selective uptake of cholesterol from plasma HDL. 7 Consequently, hepatic overexpression of SR-BI results in decreased plasma HDL cholesterol levels, [8][9][10] whereas SR-BI knockout mice have increased plasma HDL cholesterol. 11,12 Interestingly, hepatocyte SR-BI appears to accelerate reverse cholesterol transport in vivo in the face of decreased plasma HDL cholesterol levels, 13 which is in line with studies demonstrating that hepatic SR-BI expression protects against atherosclerosis development in mouse models.…”

“…14,15 Hepatic SR-BI expression is also linked to biliary cholesterol secretion in a process that is less well understood than selective uptake. Hepatic overexpression of SR-BI has been associated with increased cholesterol secretion into bile, 8,9 whereas biliary cholesterol secretion in SR-BI knockout mice is decreased. 16 However, it is not clear if SR-BI modifies intracellular cholesterol fluxes via increased selective uptake to promote biliary cholesterol secretion or if the SR-BI protein under certain conditions directly contributes to biliary cholesterol secretion in its role as an efflux transporter.…”

Down-regulation of hepatic and intestinal Abcg5 and Abcg8 expression associated with altered sterol fluxes in rats with streptozotocin-induced diabetes

“…Theoretically, hyposecretion could be explained by a lack of bile-destined cholesterol in the liver. It has been proposed that HDL cholesterol is a primary source of biliary cholesterol after its selective uptake by SR-BI [32]. One study [33] reported biliary cholesterol hyposecretion in SR-BI-deficient mice while another [34] reported hypersecretion in mice with hepatic SR-BI over-expression.…”

Intracellular cholesterol transport proteins enhance hydrolysis of HDL-CEs and facilitate elimination of cholesterol into bile

“…At this moment, it is not established whether the pools of HDL-FC and FC generated by CEH-mediated hydrolysis of HDL-CE equilibrate within the hepatocyte. FC released following hydrolysis of HDL-CE can have multiple fates (numbered [1][2][3][4], where fates 1 and 2 will result in resecretion of HDL-derived cholesterol and fates 3 and 4 will lead to final elimination of HDL-derived cholesterol in bile. Data presented here (Fig.…”