title: 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).
  
  
  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.
authors.affiliation: Department of Biology and Heart Institute, San Diego State University, San Diego, CA 92182, USA.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Gutierrez
authors.forename: Eric P
authors.initials: EP
authors.lastname: Ratliff
authors.forename: Allen M
authors.initials: AM
authors.lastname: Andres
authors.forename: Xinqiang
authors.initials: X
authors.lastname: Huang
authors.forename: Wallace L
authors.initials: WL
authors.lastname: McKeehan
authors.forename: Roger A
authors.initials: RA
authors.lastname: Davis
mesh_terms: D000818:Animals; D043303:Aryldialkylphosphatase / Q000235:genetics*; D050197:Atherosclerosis / Q000378:metabolism* / Q000503:physiopathology; D001647:Bile Acids and Salts / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004036:Diet, Atherogenic; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D008075:Lipoproteins, HDL / Q000097:blood*; D008099:Liver / Q000187:drug effects / Q000502:physiology; D008113:Liver Neoplasms; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000378:metabolism; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D043303:Aryldialkylphosphatase; D001647:Bile Acids and Salts; D002790:Cholesterol 7-alpha-Hydroxylase; D004268:DNA-Binding Proteins; D008075:Lipoproteins, HDL; D012333:RNA, Messenger; D051499:Receptor, Fibroblast Growth Factor, Type 4; D018160:Receptors, Cytoplasmic and Nuclear; D051197:Toll-Like Receptor 4; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C493487:Tlr4 protein, mouse; C502772:Cyp7a1 protein, mouse; C496372:Fgfr4 protein, mouse