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Papers In Press, published online ahead of print February 1, 2009
J. Lipid Res., doi:10.1194/jlr.M800323-JLR200

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Journal of Lipid Research, Vol. 50, 193-203, February 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

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

Helen B. Hartman, KehDih Lai and Mark J. Evans¹

Cardiovascular and Metabolic Disease Research, Wyeth Research, Collegeville, PA 19426

The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of two figures and a table.

Published, JLR Papers in Press, September 26, 2008.

¹ To whom correspondence should be addressed. e-mail: Evans.mark.mje{at}gmail.com

Multiple studies suggest increased conversion of cholesterol to bile acids by cholesterol 7-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.

Supplementary key words SHP • farnesoid X receptor • FXR • CYP7A1

Abbreviations: apoE, apolipoprotein E; chol/CA, cholesterol/cholic acid; CYP7A1, cholesterol 7-hydroxylase; CYP8B1, sterol 12 -hydroxylase; FGF-15, fibroblast growth factor-15; FPLC, Fast protein liquid chromatography; FXR, farnesoid X receptor; IBABP, ileal bile acid binding protein; LDLR, low density lipoprotein receptor; LRH-1, liver receptor homolog-1; LXR, liver X receptor; PXR, pregnane X receptor; SHP, small heterodimer partner; TG, triglyceride; WT, wild-type

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				H. B. Hartman, S. J. Gardell, C. J. Petucci, S. Wang, J. A. Krueger, and M. J. Evans Activation of farnesoid X receptor prevents atherosclerotic lesion formation in LDLR-/- and apoE-/- mice J. Lipid Res., June 1, 2009; 50(6): 1090 - 1100. [Abstract] [Full Text] [PDF]