Abstract
Cholesterol is required for maintenance of plasma membrane fluidity and integrity and for many cellular functions. Cellular cholesterol can be obtained from lipoproteins in a selective pathway of HDL-cholesteryl ester (CE) uptake without parallel apolipoprotein uptake. Scavenger receptor B type 1 (SR-B1) is a cell surface HDL receptor that mediates HDL-CE uptake. It is most abundantly expressed in liver, where it provides cholesterol for bile acid synthesis, and in steroidogenic tissues, where it delivers cholesterol needed for storage or steroidogenesis in rodents. SR-B1 transcription is regulated by trophic hormones in the adrenal gland, ovary, and testis; in the liver and elsewhere, SR-B1 is subject to posttranscriptional and posttranslational regulation. SR-B1 operates in several metabolic processes and contributes to pathogenesis of atherosclerosis, inflammation, hepatitis C virus infection, and other conditions. Here, we summarize characteristics of the selective uptake pathway and involvement of microvillar channels as facilitators of selective HDL-CE uptake. We also present the potential mechanisms of SR-B1-mediated selective cholesterol transport; the transcriptional, posttranscriptional, and posttranslational regulation of SR-B1; and the impact of gene variants on expression and function of human SR-B1. A better understanding of this unique pathway and SR-B1's role may yield improved therapies for a wide variety of conditions.
Highlights
Cholesterol is required for maintenance of plasma membrane fluidity and integrity and for many cellular functions
This cholesterol is obtained from plasma lipoproteins by a unique pathway in which circulating lipoproteins bind to the surface of the biosynthetic cells and contribute their cholesteryl esters (CEs) to the cells by a process known as the “selective” cholesterol uptake pathway [3]
The selective pathway operates in isolated hepatocytes [7, 19, 20], fibroblasts [19, 20], adipocytes [21, 22], macrophages [23, 24], and adrenal [7, 11, 19, 25], ovarian [12, 13] and Abbreviations: AcLDL, acetylated LDL; CD36, cluster determinant 36; CE, cholesteryl ester; CLA-1, cluster determinant 36 and lysosomal integral membrane protein II analogous-I; eNOS, endothelial nitric oxide synthase; 17 -E2, 17 -ethinyl estradiol; FC, free cholesterol; high density lipoprotein (HDL)-C, HDL cholesterol; LIMP, lysosomal integral membrane protein; LPS, lipopolysaccharide; OxLDL, oxidized LDL; PREB, prolactin regulatory element-binding protein; SF-1, steroidogenic factor-1; salt-inducible kinase 1 (SIK1), salt-inducible kinase; Scavenger receptor B type 1 (SR-B1), scavenger receptor B type 1; TG, triglyceride; 3′ UTR, 3′ untranslated region
Summary
Cholesterol is required for maintenance of plasma membrane fluidity and integrity and for many cellular functions. There are two binding sites for SREBP-1 that mediate positive regulation of Scarb1 expression in steroidogenic tissue and parenchymal liver cells when cellular cholesterol is depleted [100]. These studies were achieved primarily by mutating cysteine residues in mouse, rat, or human SR-B1 individually or in certain combinations to either Ser or Gly, and subsequent expression of individual constructs in cultured cells followed by determination of receptor activity, subcellular distribution of receptor protein, or selective lipid transport function.
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