A targeted mutation in the murine gene encoding the high density lipoprotein (HDL) receptor scavenger receptor class B type I reveals its key role in HDL metabolism

Abstract

Plasma high density lipoprotein (HDL), which protects against atherosclerosis, is thought to remove cholesterol from peripheral tissues and to deliver cholesteryl esters via a selective uptake pathway to the liver (reverse cholesterol transport) and steroidogenic tissues (e.g., adrenal gland for storage and hormone synthesis). Despite its physiologic and pathophysiologic importance, the cellular metabolism of HDL has not been well defined. The class B, type I scavenger receptor (SR-BI) has been proposed to play an important role in HDL metabolism because (i) it is a cell surface HDL receptor which mediates selective cholesterol uptake in cultured cells, (ii) its physiologically regulated expression is most abundant in the liver and steroidogenic tissues, and (iii) hepatic overexpression dramatically lowers plasma HDL. To test directly the normal role of SR-BI in HDL metabolism, we generated mice with a targeted null mutation in the SR-BI gene. In heterozygous and homozygous mutants relative to wild-type controls, plasma cholesterol concentrations were increased by Ϸ31% and 125%, respectively, because of the formation of large, apolipoprotein A-I (apoA-I)-containing particles, and adrenal gland cholesterol content decreased by 42% and 72%, respectively. The plasma concentration of apoA-I, the major protein in HDL, was unchanged in the mutants. This, in conjunction with the increased lipoprotein size, suggests that the increased plasma cholesterol in the mutants was due to decreased selective cholesterol uptake. These results provide strong support for the proposal that in mice the gene encoding SR-BI plays a key role in determining the levels of plasma lipoprotein cholesterol (primarily HDL) and the accumulation of cholesterol stores in the adrenal gland. If it has a similar role in controlling plasma HDL in humans, SR-BI may inf luence the development and progression of atherosclerosis and may be an attractive candidate for therapeutic intervention in this disease.

Absence of HDL cholesteryl ester uptake in mice via SR-BI impairs an adequate adrenal glucocorticoid-mediated stress response to fasting

“…No change in plasma free fatty acid or phospholipid levels was seen as a result of SR-BI deficiency ( Table 3). Plasma free cholesterol and cholesteryl ester levels were increased by 4-fold (P , 0.001) and 2.3-fold (P , 0.001) in SR-BI-deficient mice (Table 3) as a result of the accumulation of large cholesterol-rich HDL particles (data not shown), as first described by the Krieger group (11).…”

“…SR-BI-deficient mice were kindly provided by Dr. M. Krieger (11). Heterozygous SR-BI-deficient mice were cross-bred to generate wild-type and homozygous progeny.…”

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.…”

Ras/Mitogen-activated Protein Kinase (MAPK) Signaling Modulates Protein Stability and Cell Surface Expression of Scavenger Receptor SR-BI

“…SR-BI is another PPAR␣ target gene that is up-regulated by PPAR␣ agonists in human and mouse macrophages to promote HDL-inducible cholesterol efflux (29). Although the role of SR-BI for cholesterol efflux in peripheral cells is not fully understood (2,30,31), SR-BI is also highly expressed in liver to regulate hepatic uptake of HDL cholesteryl esters for excretion into bile (2,(32)(33)(34)(35). Surprisingly, in hepatocytes PPAR␣ activation induces SR-BI protein degradation and reduces SR-BI cell surface expression (36,37).…”