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Papers In Press, published online ahead of print June 1, 2009
J. Lipid Res., doi:10.1194/jlr.M800619-JLR200

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Journal of Lipid Research, Vol. 50, 1090-1100, June 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

Activation of farnesoid X receptor prevents atherosclerotic lesion formation in LDLR^–/– and apoE^–/– mice

Helen B. Hartman^*, Stephen J. Gardell^*, Chris J. Petucci, Shuguang Wang^*, Julie A. Krueger^* and Mark J. Evans^1,*

^* Cardiovascular and Metabolic Disease Research, Wyeth Research, Collegeville, PA 19426
Chemical and Screening Sciences, Wyeth Research, Collegeville, PA 19426

Published, JLR Papers in Press, January 27, 2009.

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

The role of farnesoid X receptor (FXR) in the development of atherosclerosis has been unclear. Here, LDL receptor (LDLR^–/–) or apolipoprotein E (apoE^–/–) female or male mice were fed a Western diet and treated with a potent synthetic FXR agonist, WAY-362450. Activation of FXR blocked diet-induced hypertriglyceridemia and elevations of non-HDL cholesterol and produced a near complete inhibition of aortic lesion formation. WAY-362450 also induced small heterodimer partner (SHP) expression and repressed cholesterol 7-hydroxylase (CYP7A1) and sterol 12 -hydroxylase (CYP8B1) expression. To determine if SHP was essential for these protective activities, LDLR^–/–SHP^–/– and apoE^–/–SHP^–/– mice were similarly treated with WAY-362450. Surprisingly, a notable sex difference was observed in these mice. In male LDLR^–/–SHP^–/– or apoE^–/–SHP^–/– mice, WAY-362450 still repressed CYP7A1 and CYP8B1 expression by 10-fold and still strongly reduced non-HDL cholesterol levels and aortic lesion area. In contrast, in the female LDLR^–/–SHP^–/– or apoE^–/–SHP^–/– mice, WAY-362450 only slightly repressed CYP7A1 and CYP8B1 expression and did not reduce non-HDL cholesterol or aortic lesion size. WAY-362450 inhibition of hypertriglyceridemia remained intact in LDLR^–/– or apoE^–/– mice lacking SHP of both sexes. These results suggest that activation of FXR protects against atherosclerosis in the mouse, and this protective effect correlates with repression of bile acid synthetic genes, with mechanistic differences between male and female mice.

Supplementary key words small heterodimer partner • cholesterol 7-hydroxylase • sterol 12 -hydroxylase • atherosclerosis

Abbreviations: apoE, apolipoprotein E; BSEP, bile salt export protein; CYP7A1, cholesterol 7-hydroxylase; CYP8B1, sterol 12 -hydroxylase; FXR, farnesoid X receptor; IBABP, ileal bile acid binding protein; LDLR, low density lipoprotein receptor; LXR, liver X receptor; PCSK9, proprotein convertase subtilisin/kexin type 9; PXR, pregnane X receptor; SHP, small heterodimer partner; TβMCA, tauro-β-muricholic acid; TCA, taurocholic acid; TCDCA, taurochenodeoxycholic acid; TG, triglyceride

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