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 7alpha-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.

• Authors: Helen B Hartman, Kehdih Lai, Mark J Evans
• Journal: Journal of lipid research (J Lipid Res) Vol. 50 Issue 2 Pg. 193-203 (Feb 2009) ISSN: 0022-2275 [Print] United States
• PMID: 18820241 (Publication Type: Journal Article)

Chemical References

• Cholesterol, LDL
• Cholesterol, VLDL
• Receptors, Cytoplasmic and Nuclear
• nuclear receptor subfamily 0, group B, member 2

Topics

• Animals
• Cholesterol, LDL (blood, metabolism)
• Cholesterol, VLDL (blood, metabolism)
• Dyslipidemias (genetics, metabolism)
• Gene Expression
• Liver (metabolism)
• Mice
• Mice, Transgenic
• Receptors, Cytoplasmic and Nuclear (genetics, metabolism)