The Role of the High-Density Lipoprotein Receptor SR-BI in the Lipid Metabolism of Endocrine and Other Tissues

Abstract

Because cholesterol is a precursor for the synthesis of steroid hormones, steroidogenic tissues have evolved multiple pathways to ensure adequate supplies of cholesterol. These include synthesis, storage as cholesteryl esters, and import from lipoproteins. In addition to endocytosis via members of the low-density lipoprotein receptor superfamily, steroidogenic cells acquire cholesterol from lipoproteins by selective lipid uptake. This pathway, which does not involve lysosomal degradation of the lipoprotein, is mediated by the scavenger receptor class B type I (SR-BI). SR-BI is highly expressed in steroidogenic cells, where its expression is regulated by various trophic hormones, as well as in the liver. Studies of genetically manipulated strains of mice have established that SR-BI plays a key role in regulating lipoprotein metabolism and cholesterol transport to steroidogenic tissues and to the liver for biliary secretion. In addition, analysis of SR-BI-deficient mice has shown that SR-BI expression is important for alpha-tocopherol and nitric oxide metabolism, as well as normal red blood cell maturation and female fertility. These mouse models have also revealed that SR-BI can protect against atherosclerosis. If SR-BI plays similar physiological and pathophysiological roles in humans, it may be an attractive target for therapeutic intervention in cardiovascular and reproductive diseases.

Impact of Aging on Steroid Hormone Biosynthesis and Secretion

“…The uptake of HDL cholesterol by steroidogenic cells, however, involves a unique pathway, termed 'selective' pathway in which cholesteryl esters (CEs) are selectively transferred to the cell interior without the parallel uptake and degradation of the HDL particle itself (Fig. 2) [33,34]. SR-BI, a multiligand cell surface receptor, binds HDL with high affinity and mediates selective cholesterol uptake [33,34].…”

“…2) [33,34]. SR-BI, a multiligand cell surface receptor, binds HDL with high affinity and mediates selective cholesterol uptake [33,34]. The selectively delivered CEs are either hydrolyzed by the neutral cholesteryl ester hydrolase (CEH) and released as cholesterol used for steroiodogenesis, or stored in cellular lipid droplets [33,35].…”

Characterization of the inhibition of hepatitis C virus entry byIn vitro-generated and patient-derived oxidized low-density lipoprotein

“…9 SR-BI is a 509-amino-acid protein with two transmembrane domains and a single large extracellular loop that is highly expressed in the liver and in tissues producing steroid hormones. 10 It is the key highdensity lipoprotein (HDL) receptor and mediates a flux of free cholesterol from the lipoprotein into the cellular membrane. 10,11 Besides HDL, SR-BI interacts with diverse other ligands, including VLDL, native LDL, oxidized LDL (oxLDL), lipopolysaccharides, TG-rich lipoprotein (TRL) remnants, and serum amyloid alpha (SAA) through multiple binding sites.…”

“…10 It is the key highdensity lipoprotein (HDL) receptor and mediates a flux of free cholesterol from the lipoprotein into the cellular membrane. 10,11 Besides HDL, SR-BI interacts with diverse other ligands, including VLDL, native LDL, oxidized LDL (oxLDL), lipopolysaccharides, TG-rich lipoprotein (TRL) remnants, and serum amyloid alpha (SAA) through multiple binding sites. 10,[12][13][14][15] First proposed as an HCV receptor because of its interaction with the viral glycoprotein, E2, 16 SR-BI was subsequently shown to be essential for HCV entry in numerous studies.…”

“…10,11 Besides HDL, SR-BI interacts with diverse other ligands, including VLDL, native LDL, oxidized LDL (oxLDL), lipopolysaccharides, TG-rich lipoprotein (TRL) remnants, and serum amyloid alpha (SAA) through multiple binding sites. 10,[12][13][14][15] First proposed as an HCV receptor because of its interaction with the viral glycoprotein, E2, 16 SR-BI was subsequently shown to be essential for HCV entry in numerous studies. 5,9,17,18 Animal data indicate that SR-BI is also important for HCV infection in vivo, 19 and an inhibitor of HCV/SR-BI interaction is the only HCVentry inhibitor currently in clinical trials.…”