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

Multiple studies suggest increased conversion of cholesterol to bile acids by cholesterol 7 alpha-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-C57B1/6 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 (LDLRSHP2/2)-S-2/2 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. - Hartman, H. B., K. Lai, and M. J. Evans. Loss of small heterodimer partner expression in the liver protects against dyslipidemia. J. Lipid Res. 2009. 50: 193-203.