Abstract 238: Serum Opacity Factor Normalizes Dysfunctional High Density Lipoproteins In Srbi -/- Female Mice And Rescues Fertility

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Although plasma HDL-C levels negatively correlate with atherosclerotic cardiovascular disease (ACVD), attempts to reduce ACVD risk by raising plasma HDL have disappointed. Thus, hypotheses about salutary HDL effects have shifted from higher-is-better to function-is-more-important. The SRBI-/- mouse is an extreme model of HDL dsyfunctionality; compared to WT mice, SRB1-/- mice have higher plasma HDL levels and an HDL surface that is free cholesterol (FC)-rich (60 vs. 15 mol%). This would be expected to increase HDL-FC bioavailability to cytotoxic levels. HDL dysfunctionality among SRB1-/- mice is associated with multiple metabolic abnormalities—impaired cell membrane structure and function and atherosusceptibility, despite having high plasma HDL-C levels, and infertility among female SRB1-/- mice. Dietary probucol, an HDL-lowering drug, partially reverses infertility in SR-B1-/- mice. The mechanisms underlying ovaritoxicity is not known and interventions that fully reverse this state has not been identified. We hypothesized that a bacterial protein, serum opacity factor (SOF), which acts on HDL and lowers cholesterol in WT mice by 43% in 3 hours, would normalize HDL functionality and rescue infertility in SRBI-/- female mice. SOF DNA was cloned into a TBG-AAV8 plasmid and virus produced by UPENN Vector Lab. The AAV-SOF was delivered by IP injection leading to the endogenous expression of SOF. Probucol-fed and AAV-GFP mice were used as controls. SOF expression drastically decreased plasma cholesterol and normalized the size of HDL in SRBI-/- females comparable to that of WT mice. Fertility was restored in female mice injected with SOF while GFP controls remained infertile. Compared to Probucol-fed mice, AAV-SOF females had a higher percentage of fertile females and shorter time to first litter drop. We concluded that SOF performed equally or better than probucol in rescuing fertility and normalizing HDL.