A role for FXR and human FGF-19 in the repression of paraoxonase-1 gene expression by bile acids.
Paraoxonase-1 (PON1), an enzyme that metabolizes organophosphate insecticides, is secreted by the liver and transported in the blood complexed to HDL. In humans and mice, low plasma levels of PON1 have also been linked to the development of atherosclerosis. We previously reported that hepatic Pon1 expression was decreased when C57BL/6J mice were fed a high-fat, high-cholesterol diet supplemented with cholic acid (CA). In the current study, we used wild-type and farnesoid X receptor (FXR) null mice to demonstrate that this repression is dependent upon CA and FXR. PON1 mRNA levels were also repressed when HepG2 cells, derived from a human hepatoma, were incubated with natural or highly specific synthetic FXR agonists. In contrast, fibroblast growth factor-19 (FGF-19) mRNA levels were greatly induced by these same FXR agonists. Furthermore, treatment of HepG2 cells with recombinant human FGF-19 significantly decreased PON1 mRNA levels. Finally, deletion studies revealed that the proximal -230 to -96 bp region of the PON1 promoter contains regulatory element(s) necessary for promoter activity and bile acid repression. These data demonstrate that human PON1 expression is repressed by bile acids through the actions of FXR and FGF-19.
Shih
Diana M
DM
Division of Cardiology, Department of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA. dshih@mednet.ucla.edu
Kast-Woelbern
Heidi R
HR
Wong
Jack
J
Xia
Yu-Rong
YR
Edwards
Peter A
PA
Lusis
Aldons J
AJ
D000284:Administration, Oral; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D043303:Aryldialkylphosphatase / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D001647:Bile Acids and Salts / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002635:Chenodeoxycholic Acid / Q000494:pharmacology; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics; D002791:Cholesterol, Dietary / Q000008:administration & dosage / Q000494:pharmacology; D019826:Cholic Acid / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000819:agonists / Q000235:genetics / Q000502:physiology*; D004041:Dietary Fats / Q000008:administration & dosage / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000502:physiology*; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D049294:Phospholipid Transfer Proteins / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics; D014157:Transcription Factors / Q000819:agonists / Q000235:genetics / Q000502:physiology*; D000099150:Receptor, Farnesoid X-Activated
D000873:Anthracenes; D043303:Aryldialkylphosphatase; D001647:Bile Acids and Salts; D002635:Chenodeoxycholic Acid; D002790:Cholesterol 7-alpha-Hydroxylase; D002791:Cholesterol, Dietary; D019826:Cholic Acid; D004268:DNA-Binding Proteins; D004041:Dietary Fats; D004791:Enzyme Inhibitors; D005346:Fibroblast Growth Factors; D007555:Isoxazoles; D048031:JNK Mitogen-Activated Protein Kinases; D049294:Phospholipid Transfer Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C117476:FGF19 protein, human; C493430:PLTP protein, human; C099713:nuclear receptor subfamily 0, group B, member 2; C432165:pyrazolanthrone; C412815:GW 4064