Overexpression of the HDL receptor SR-BI alters plasma HDL and bile cholesterol levels

Abstract

The risk of atherosclerosis, a leading cause of cardiovascular disease and death, is inversely related to plasma levels of high-density lipoprotein (HDL) cholesterol, although the mechanism of this protective effect is unclear. The class B scavenger receptor, SR-BI, is the first HDL receptor to be well defined at a molecular level and is a mediator of selective cholesterol uptake in vitro. It is expressed most abundantly in steroidogenic tissues, where it is coordinately regulated with steroidogenesis by adrenocorticotropic hormone (ACTH), human chorionic gonadotropin (hCG) and oestrogen, and in the liver, where its expression in rats is suppressed by oestrogen. Here we show that adenovirus-mediated, hepatic overexpression of SR-BI in mice on both sinusoidal and canalicular surfaces of hepatocytes results in the virtual disappearance of plasma HDL and a substantial increase in biliary cholesterol. SR-BI may directly mediate these effects by increasing hepatic HDL cholesterol uptake or by increasing cholesterol secretion into bile, or both. These results indicate that SR-BI may be important in hepatic HDL metabolism, in determining plasma HDL concentrations, and in controlling cholesterol concentrations in bile, and thus may influence the development and progression of atherosclerosis and gallstone disease.

Scavenger receptor class B type I mediates biliary cholesterol secretion independent of ATP-binding cassette transporter g5/g8 in mice

“…8 Therefore, we performed continuous bile cannulation to assess biliary sterol secretion rates (Table 2; for values normalized to liver weight, see Supporting Table 3). Bile flow was significantly increased in response to SR-BI overexpression (P Ͻ 0.001).…”

“…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

“…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. We found that plasma HDL cholesterol and apo A-I levels were increased in diabetic rats, as is the case in SR-BI-deficient mice [33].…”