Serum opacity factor normalizes dysfunctional HDL phenotype in SRB1 -/- mice

Abstract

Background and Aims: Although plasma HDL-C levels negatively correlate with atherosclerotic cardiovascular disease (ACVD), attempts to reduce ACVD risk by raising plasma HDL have disappointed. The SRB1-/- mouse is an extreme model of HDL dsyfunctionality; compared to WT mice, SRB1-/- mice have higher plasma HDL with a free cholesterol (FC)-rich surface (60 vs. 15 mol%). HDL dysfunctionality among SRB1-/- mice is associated with atherosusceptibility and female infertility. Liver-specific SRB1 expression in SRB1-/- mice normalizes HDL size and FC content. Thus, the SRB1-/- mouse phenotype is due to lack of hepatic clearance of dysfunctional HDL. Serum opacity factor (SOF) is a bacterial protein that catalyzes the quantitative disproportionation of HDL into a cholesteryl ester-rich micro emulsion (CERM), neo HDL, and lipid-free apo AI. The CERM contains apo E and all HDL-CE. Injection of SOF into WT mice lowers plasma cholesterol by diverting the CERM to hepatic LDLR. Our studies will determine whether normalizing dysfunctional HDL in SRB1-/- mice by SOF leads to phenotypical changes in female infertility and atherosclerosis in a high-fat diet model.