Functional genomics of the human high-density lipoprotein receptor scavenger receptor BI: an old dog with new tricks

Purpose of review The athero-protective role of scavenger receptor BI (SR-BI) is primarily attributed to its ability to selectively transfer cholesteryl esters from high-density lipoproteins (HDLs) to the liver during reverse cholesterol transport (RCT). In this review, we highlight recent findings that reveal the impact of SR-BI on lipid levels and cardiovascular disease in humans. Moreover, additional responsibilities of SR-BI in modulating adrenal and platelet function, as well as female fertility in humans, are discussed. Recent findings Heterozygote carriers of P297S, S112F and T175A-mutant SR-BI receptors were identified in patients with high HDL-cholesterol levels. HDL from P297S-SR-BI carriers was unable to mediate macrophage cholesterol efflux, whereas hepatocytes expressing P297S-SR-BI were unable to mediate the selective uptake of HDL-cholesteryl esters. S112F and T175A-mutant receptors exhibited similar impaired cholesterol transport functions in vitro. Reduced SR-BI function in P297S carriers was also associated with decreased steroidogenesis and altered platelet function. Further, human population studies identified SCARB1 variants associated with female infertility. Summary Identification of SR-BI variants confirms the key role of this receptor in influencing lipid levels and RCT in humans. A deeper understanding of the contributions of SR-BI to steroidogenesis, platelet function and fertility is required in light of exploration of HDL-raising therapies aimed at reducing cardiovascular risk.