Loss of small heterodimer partner expression in the liver protects against dyslipidemias⃞

Abstract

Multiple studies suggest increased conversion of cholesterol to bile acids by cholesterol 7α-hydroxylase (CYP7A1) protects against dyslipidemia and atherosclerosis. CYP7A1 expression is repressed by the sequential activity of two nuclear hormone receptors, farnesoid X receptor (FXR) and small heterodimer partner (SHP). Here we demonstrate 129 strain SHP−/− mice are protected against hypercholesterolemia resulting from either a cholesterol/cholic acid (chol/CA) diet or from hypothyroidism. In a mixed 129-C57Bl/6 background, LDLR−/− and LDLR−/−SHP−/− mice had nearly identical elevations in hepatic cholesterol content and repression of cholesterol regulated genes when fed a Western diet. However, the LDLR−/−SHP−/− mice had greatly reduced elevations in serum VLDL and LDL cholesterol levels and triglyceride (TG) levels as compared with LDLR−/− mice. Additionally, the hepatic inflammation produced by the Western diet in the LDLR−/− mice was abolished in the LDLR−/−SHP−/− mice. CYP7A1 expression was induced 10-fold by the Western diet in the LDLR−/−SHP−/− mice but not in the LDLR−/− mice. Finally, hepatocyte-specific deletion of SHP expression was also protective against dyslipidemia induced by either a chol/CA diet or by hypothyroidism. While no antagonist ligands have yet been identified for SHP, these results suggest selective inhibition of hepatic SHP expression may provide protection against dyslipidemia.

Keywords

• SHP
• farnesoid X receptor
• FXR
• CYP7A1