Abstract 499: Serum Opacity Factor Therapy Alters Plasma, Erythrocyte And Tissue Cholesterol Content In The Dysfunctional High Density Lipoprotein Scarb1 ^-/- Mouse Model

Aim: In humans, very high plasma HDL-cholesterol concentrations are associated with increased all cause- and atherosclerotic cardiovascular disease (ASCVD)-mortality. The HDL receptor-deficient mouse (Scarb1 -/- ) is a robust model of this phenotype having high free cholesterol (FC) bioavailability due to too many FC-rich HDL particles. Clinically, plasma LDL and HDL are quantified according to total cholesterol = FC + cholesteryl esters (CE), which likely contribute to ASCVD pathophysiology differently. Despite higher HDL, Scarb1 -/- mice have more ASCVD on a Western diet, and increased mol% FC in ovaries, erythrocytes, heart, lung, female liver and macrophages, tissues that are associated with female infertility, impaired cell maturation, cardiac dysfunction and atherosclerosis. Bacterial serum opacity factor (SOF) reduces plasma cholesterol ~ 40% by diverting HDL-cholesterol to the hepatic LDLR. Hypothesis: Adeno-associated virus delivery of SOF (AAV SOF ) normalizes plasma and tissue FC accretion and reverses the pathologies associated with Scarb1 -/- mice. Methods: The lipid compositions of plasma, HDL, erythrocytes, and tissues of Scarb1 -/- mice treated with AAV SOF at 12-13 weeks of age for three weeks were compared with age- and sex-matched wild type (WT) C57BL6 and Scarb1 -/- mice. Results: As hypothesized, AAV SOF reduced plasma and HDL-FC and CE, as well as mol% FC in Scarb1 -/- mice towards WT levels. Erythrocyte FC levels also fell, but mol% FC remained elevated. Some changes were sex-specific: AAV SOF reduced the elevated FC only in female livers to WT levels. AAV SOF reduced FC and CE in lungs of females to WT levels, but not among males; the mol% FC remained high in both sexes. In steroidogenic tissues, adrenals, ovaries and testis, AAV SOF treatment increased FC. Unexpectedly, in Scarb1 -/- mice, AAV SOF increased mol% FC and FC in heart beyond already elevated levels. Conclusions: These findings support the hypothesis that plasma and HDL cholesterol levels determine tissue cholesterol levels that drive the pathologies specific to Scarb1 -/- mice. This evolving model of the role of HDL-FC in RCT provides a rationale for human studies to determine the utility of HDL-FC bioavailability as a risk factor for ASCVD and other pathologies.