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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:301.)
© 2006 American Heart Association, Inc.

Vascular Biology

Bile Acids Decrease Hepatic Paraoxonase 1 Expression and Plasma High-Density Lipoprotein Levels Via FXR-Mediated Signaling of FGFR4

Alejandra Gutierrez; Eric P. Ratliff; Allen M. Andres; Xinqiang Huang; Wallace L. McKeehan; Roger A. Davis

From the Department of Biology and Heart Institute (A.G., E.P.R., A.M.A., R.A.D.), San Diego State University, San Diego, Calif.; and the Center for Cancer Biology and Nutrition (X.H., W.L.M.), Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston, Tex.

Correspondence to Roger A. Davis, Department of Biology, LS307, San Diego State University, 5500 Campanile Dr, San Diego, CA 92182. E-mail rdavis{at}sunstroke.sdsu.edu

Objective— The purpose of this research was to determine how dietary bile acids repress hepatic expression of paraoxonase 1 (PON1).

Methods and Results— C57BL/6 mice and C3H/HeJ mice, having different susceptibilities to atherosclerosis, were fed a chow diet and an atherogenic diet containing taurocholate. Compared with the more atherosclerosis–susceptible C57BL/6 mice, C3H/HeJ mice display resistance to dietary bile acid repression of hepatic PON1 mRNA and decreased high-density lipoprotein cholesterol. Whereas knockout of toll receptor 4 did not affect response to taurocholate, deletion of either FXR or FGFR4 blocked taurocholate repression of PON1 and CYP7A1. FGF19, an activator of FGFR4 expressed in human ileum, decreased expression of both PON1 and CYP7A1 expression by human hepatoma cells. In all of the mice studied, dietary taurocholate increased ileal expression of FGF15, a FXR-inducible murine homologue of human FGF19.

Conclusions— Hepatic PON1 and CYP7A1 mRNA expression is repressed by bile acids via FXR-mediated induction of FGF15. Thus, the inability of C3H/HeJ mice to display taurocholate repression of PON1 and CYP7A1 mRNAs was not because of a lack of induction of FGF15 but rather signaling events distal to FGF15-FGFR4 association.

Experiments using genetically modified mice show that bile acid activation of FXR induces ileal expression of FGF15, which, through signaling of hepatic receptor FGFR4, reduces PON1 and CYP7A1 mRNAs and high-density lipoprotein cholesterol while enhancing susceptibility to atherosclerosis.

Key Words: paraoxonase1 • HDL • FXR • FGF15 • FGFR4

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