title: Antagonism of the actions of peroxisome proliferator-activated receptor-alpha by bile acids.
abstract: The peroxisome proliferator-activated receptor-alpha (PPARalpha) is a ligand-activated transcription factor that regulates the expression of a number of genes critical for fatty acid beta-oxidation. Because a number of substrates and intermediates of this metabolic pathway serve as ligand activators of this receptor, homeostatic control of fatty acid metabolism is achieved. Evidence also exists for PPARalpha-dependent regulation of genes encoding critical enzymes of bile acid biosynthesis. To determine whether the primary products of bile acid biosynthesis, cholic acid and chenodeoxycholic acid, were capable of modulating PPARalpha function, a variety of in vivo and in vitro approaches were utilized. Feeding a bile acid-enriched diet significantly reduced the degree of hepatomegaly and induction of target genes encoding enzymes of fatty acid beta-oxidation caused by treatment with the potent PPARalpha ligand Wyeth-14,643. Convergent data from mechanistic studies indicate that bile acids interfere with transactivation by PPARalpha at least in part by impairing the recruitment of transcriptional coactivators. The results of this study provide the first evidence in favor of the existence of compounds, normally found within the body, that are capable of antagonizing the physiological actions of PPARalpha. The impact of PPARalpha antagonism by endogenous bile acids is likely to be limited under normal conditions and to have only minimal effects on bile acid homeostasis. However, during certain pathophysiological states where intracellular bile acid concentrations are elevated, meaningful effects on PPARalpha-dependent target gene regulation are possible.
authors.affiliation: Laboratory of Metabolism, Division of Basic Sciences, NCI, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: C J
authors.initials: CJ
authors.lastname: Sinal
authors.forename: M
authors.initials: M
authors.lastname: Yoon
authors.forename: F J
authors.initials: FJ
authors.lastname: Gonzalez
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D002460:Cell Line; D002635:Chenodeoxycholic Acid / Q000737:chemistry / Q000494:pharmacology; D019826:Cholic Acid / Q000737:chemistry / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005765:Gastrointestinal Agents / Q000737:chemistry / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D008024:Ligands; D051379:Mice; D008822:Mice, Transgenic; D009153:Mutagens / Q000737:chemistry / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism; D010957:Plasmids; D014176:Protein Biosynthesis; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D002635:Chenodeoxycholic Acid; D019826:Cholic Acid; D004268:DNA-Binding Proteins; D005765:Gastrointestinal Agents; D008024:Ligands; D009153:Mutagens; D010100:Oxygen; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C006253:pirinixic acid