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Impact of gene variants on sex-specific regulation of human Scavenger receptor class B type 1 (SR-BI) expression in liver and association with lipid levels in a population-based study

DOI: 10.1186/1471-2350-11-9

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Abstract:

We utilized both epidemiological and molecular methods to study how estrogen and gene variants interact to influence SCARB1 expression and lipid levels. Interaction between 35 SCARB1 haplotype-tagged polymorphisms and endogenous estradiol levels was assessed in 498 postmenopausal Caucasian women from the population-based Rancho Bernardo Study. We further examined associated variants with overall and SCARB1 splice variant (SR-BI and SR-BII) expression in 91 human liver tissues using quantitative real-time PCR.Several variants on a haplotype block spanning intron 11 to intron 12 of SCARB1 showed significant gene by estradiol interaction affecting serum lipid levels, the strongest for rs838895 with HDL-cholesterol (p = 9.2 × 10-4) and triglycerides (p = 1.3 × 10-3) and the triglyceride:HDL cholesterol ratio (p = 2.7 × 10-4). These same variants were associated with expression of the SR-BI isoform in a sex-specific fashion, with the strongest association found among liver tissue from 52 young women <45 years old (p = 0.002).Estrogen and SCARB1 genotype may act synergistically to regulate expression of SCARB1 isoforms and impact serum levels of HDL cholesterol and triglycerides. This work highlights the importance of considering sex-dependent effects of gene variants on serum lipid levels.The scavenger receptor class B type 1 (SR-BI) is a plasma membrane protein that binds high density lipoprotein (HDL) with high affinity and mediates selective uptake of cholesterol esters by the liver[1,2]. Besides its role as a functional HDL receptor involved in reverse cholesterol transport, SR-BI also participates in the metabolism of Apolipoprotein B-containing lipoproteins, including low density lipoprotein (LDL)[3,4] and very low density lipoprotein (VLDL)[5,6]. In addition, studies have implicated SR-BI as a key co-receptor mediating infection with the hepatitis C virus[7], where chronic infection is characterized by marked lipid changes reflecting viral dependence on host lipid

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