title: 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.affiliation: Cardiovascular and Metabolic Disease Research, Wyeth Research, Collegeville, PA 19426, USA.
authors.forename: Helen B
authors.initials: HB
authors.lastname: Hartman
authors.forename: Kehdih
authors.initials: K
authors.lastname: Lai
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Evans
mesh_terms: D000818:Animals; D008078:Cholesterol, LDL / Q000097:blood / Q000378:metabolism; D015243:Cholesterol, VLDL / Q000097:blood / Q000378:metabolism; D050171:Dyslipidemias / Q000235:genetics* / Q000378:metabolism*; D015870:Gene Expression; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism
chemical_list: D008078:Cholesterol, LDL; D015243:Cholesterol, VLDL; D018160:Receptors, Cytoplasmic and Nuclear; C099713:nuclear receptor subfamily 0, group B, member 2