Abstract 392: Loss of SHP Protects LDLRKO from Diet-induced Hypercholesterolemia
CYP7A1 encodes the rate limiting enzyme for the conversion of cholesterol to bile acids. Several studies have demonstrated that elevated expression of CYP7A1 confers protection from hypercholesterolemia. CYP7A1 expression is regulated by two nuclear receptors, farnesoid X receptor (FXR) and small heterodimer (SHP). Here we demonstrate that although FXR−/ − and SHP−/ − mice have similarly elevated levels of CYP7A1, FXR−/ − mice have elevated serum cholesterol and triglyceride levels and serum markers of hepatic inflammation whereas the SHP−/ − mice do not. This suggestion of a beneficial lipid effect of the loss of SHP was confirmed in a cholesterol/cholic acid diet model, in which SHP−/ − mice were strongly protected form diet-induced hypercholesterolemia and hepatic inflammation. To examine the effects of the loss of SHP in a model relevant to human dyslipidemia, we generated LDLR−/ −SHP−/ − mice. The LDLR−/ −SHP−/ − mice were highly resistant to Western diet-induced elevation in serum VLDL and LDL cholesterol levels and had significantly increased levels of HDL cholesterol as compared to LDLR−/ − mice fed the Western diet. Further, hepatic inflammatory gene expression induced by the Western diet was abolished in the LDLR−/ −SHP−/ − mice. Surprisingly, the LDLR−/ − and LDLR−/ −SHP−/ − mice had nearly identical elevations in hepatic cholesterol content and repression of cholesterol regulated genes such as HMG CoA synthase and PCSK9. CYP7A1 expression was induced 10-fold by Western in the LDLR−/ −SHP−/ − mice but not in the LDLR−/ −. The Western diet induction of CYP7A1 expression in the LDLR−/ −SHP−/ − mice as compared to the LDLR−/ − (containing an intact FXR/SHP negative pathway to modulate CYP7A1 expression) may provide a basis for the protection of LDLR−/ −SHP−/ − mice, and suggests potential utility of SHP antagonists in dyslipidemia.