Targeted mutation reveals a central role for SR-BI in hepatic selective uptake of high density lipoprotein cholesterol

Abstract

Scavenger receptor BI (SR-BI) is a cell surface receptor that binds high density lipoproteins (HDL) and mediates selective uptake of HDL cholesteryl esters (CE) in transfected cells. To address the physiological role of SR-BI in HDL cholesterol homeostasis, mice were generated bearing an SR-BI promoter mutation that resulted in decreased expression of the receptor in homozygous mutant (designated SR-BI att) mice. Hepatic expression of the receptor was reduced by 53% with a corresponding increase in total plasma cholesterol levels of 50-70% in SR-BI att mice, attributable almost exclusively to elevated plasma HDL. In addition to increased HDL-CE, HDL phospholipids and apo A-1 levels were elevated, and there was an increase in HDL particle size in mutant mice. Metabolic studies using HDL bearing nondegradable radiolabels in both the protein and lipid components demonstrated that reducing hepatic SR-BI expression by half was associated with a decrease of 47% in selective uptake of CE by the liver, and a corresponding reduction of 53% in selective removal of HDL-CE from plasma. Taken together, these findings strongly support a pivotal role for hepatic SR-BI expression in regulating plasma HDL levels and indicate that SR-BI is the major molecule mediating selective CE uptake by the liver. The inverse correlation between plasma HDL levels and atherosclerosis further suggests that SR-BI may inf luence the development of coronary artery disease.It is well established that plasma concentrations of high density lipoprotein (HDL) cholesterol are inversely proportional to the risk of developing atherosclerosis and coronary artery disease (1). Although the protective mechanism is not known, HDL is thought to reduce plaque formation by removing cholesterol from arterial cells and delivering it to the liver as cholesteryl ester (CE) for bile acid synthesis and secretion, a process referred to as reverse cholesterol transport (2). HDL also delivers CE to steroidogenic tissues (adrenal gland, ovary, and testis), where it serves as substrate for steroid hormone synthesis (reviewed in ref.3). The uptake of HDL cholesterol by cells involves selective transfer of CE to the cell without uptake and degradation of HDL proteins, a process known as selective lipid uptake (4, 5). This is markedly different from the mechanism of clearance of low density lipoproteins (LDL), which involves receptor-mediated endocytosis and intracellular degradation of the entire lipoprotein particle (6).Whereas the receptor that mediates LDL clearance was identified well over a decade ago (6), a functional HDL receptor has only recently been identified. Acton et al. (7) demonstrated that scavenger receptor BI (SR-BI), a multiligand cell surface receptor isolated from Chinese hamster ovary cells by expression cloning (8), binds HDL with high affinity and mediates selective cholesterol uptake in transfected cells. Furthermore, the receptor is primarily expressed in those tissues exhibiting selective lipid uptake in vivo: liver, adrenal gland, ovary, ...

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

“…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.…”

Bioinformatic analysis of endogenous and exogenous small RNAs on lipoproteins

“…Loss-of-function variants in human SCARB1 (SR-BI) were associated with increased in circulating HDL-C levels [37]. Likewise, Scarb1 mutations in mice also resulted in increased HDL-C levels [38]. We have previously reported that HDL-delivery of miRNAs to hepatocytes in vitro requires SR-BI [13].…”

Biliary cholesterol hypersecretion in gallstone-susceptible mice is associated with hepatic up-regulation of the high-density lipoprotein receptor SRBI

“…Overexpression of SRBI following infection with recombinant adenoviruses or in transgenic mice resulted in reductions in plasma HDL cholesterol [36][37][38][39] and was associated with a substantial increase in the cholesterol content of gallbladder and hepatic biles. 38,40 Disruption of the Srb1 gene promoter with subsequently decreased SRBI protein expression increased plasma HDL levels 41 and decreased biliary cholesterol. 40 The close linkage of biliary cholesterol and SRBI protein expression is further supported by a negative correlation between the cholesterol content of bile and HDL levels.…”