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

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, hepatocytespecific deletion of SHP expression was also protective against dyslipidemia. Copyright © 2009 by the American Society for Biochemistry and Molecular Biology, Inc.