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

Abstract

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. M ultiple case-controlled studies of humans show an inverse relationship among the plasma activity of paraoxonase 1 (PON1), the formation of atherosclerotic lesions, and myocardial infarction. [1][2][3][4][5][6] Thus, plasma levels of PON1 accurately predict susceptibility to atherosclerosis.PON1 is mainly expressed in the liver 7 and displays the unusual characteristic of being secreted with an intact N-terminal signal sequence. 8 PON1 exhibits multiple enzyme activities including acting as an organophosphate esterase, a carboxyl esterase, 9,10 a lactonase, 11,12 and a phospholipase A2. 13,14 The latter activity has been proposed to play an important role in inactivating the proatherogenic inflammatory lipids produced by the oxidative modification of lowdensity lipoprotein. 15 Most of the PON1 present in plasma is associated with high-density lipoprotein (HDL), which may explain the well-established atheroprotective effect of HDL. 13,16,17 The antiinflammatory properties of HDL are dependent, at least in part, on the presence of PON1. 13 Dissociation of PON1 from HDL causes the HDL particle to become atherogenic. 13 Studies using inbred strains of mice showed that a cholic acid-containing atherogenic diet reduced the hepatic expression of both PON1 and CYP7A1 mRNAs and plasma HDL cholesterol levels in atherosclerosis-susceptible C57BL/6 mice but not in atherosclerosis-resistant C3H/HeJ mice. 18 Additional analysis of a subset of recombinant inbred strains derived from the B6 and C3H parental strains showed that the ability of the cholic acid-containing atherogenic diet to decrease hepatic PON1 mRNA expression segregated with aortic lesion development. 18 In a similar subset of recombinant progeny from B6 and C3H parental strains, HDL levels were linked to 3 individual gene...

Differential regulation of bile acid homeostasis by the farnesoid X receptor in liver and intestine

“…5, 6). The potential role of the FXR-FGF15 signaling cascade in regulating gene expression was further investigated by analyzing the hepatic expression of paraoxonase 1 (PON1), which is regulated by FGF15 (35,36). PON1 mRNA levels were significantly reduced by GW4064 in control and Fxr DL mouse liver but not in liver of Fxr DIE mice (Figs.…”

Deletion of the ileal basolateral bile acid transporter identifies the cellular sentinels that regulate the bile acid pool

“…Uptake of bile acids that activate FXR by the ileal enterocyte induces the expression of fibroblast growth factor is (FGF15) (11)(12)(13). FGF15 is released into the portal circulation and then binds to the hepatocyte basolateral receptor FGFR4, leading to the repression of Cyp7A1 expression (8,(12)(13)(14)(15). In short, FGF15 is the link between FXR sensing of bile acids in enterocytes and expression of Cyp7A1 in hepatocytes.…”

Resolving the mechanism of bile acid negative-feedback regulation, a Journal of Lipid Research tradition

“…The other SHP-1-independent mechanism involves activation of the tyrosine kinase associated with fibroblast growth factor receptor 4 (FGFR4) (13). The FGFR4 ligands responsible for initiating repression of CYP7A1 are FGF15 (mouse) and FGF19 (human), which are both produced by intestinal ileal cells (14)(15)(16). The discovery that intestinal expression of FGF19 (17) and FGF15 (18) is induced by activation of FXR explains why bile acid negativefeedback regulation of CYP7A1 could not be reproduced in cell culture systems consisting only of hepatic parenchymal cells (19).…”