title: Regulation of human class I alcohol dehydrogenases by bile acids.
abstract: Class I alcohol dehydrogenases (ADH1s) are the rate-limiting enzymes for ethanol and vitamin A (retinol) metabolism in the liver. Because previous studies have shown that human ADH1 enzymes may participate in bile acid metabolism, we investigated whether the bile acid-activated nuclear receptor farnesoid X receptor (FXR) regulates ADH1 genes. In human hepatocytes, both the endogenous FXR ligand chenodeoxycholic acid and synthetic FXR-specific agonist GW4064 increased ADH1 mRNA, protein, and activity. Moreover, overexpression of a constitutively active form of FXR induced ADH1A and ADH1B expression, whereas silencing of FXR abolished the effects of FXR agonists on ADH1 expression and activity. Transient transfection studies and electrophoretic mobility shift assays revealed functional FXR response elements in the ADH1A and ADH1B proximal promoters, thus indicating that both genes are direct targets of FXR. These findings provide the first evidence for direct connection of bile acid signaling and alcohol metabolism.
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Pharmacy and Institute of Biomedicine of University of Barcelona, Barcelona, Spain.
authors.forename: Cédric
authors.initials: C
authors.lastname: Langhi
authors.forename: Elena
authors.initials: E
authors.lastname: Pedraz-Cuesta
authors.forename: Diego
authors.initials: D
authors.lastname: Haro
authors.forename: Pedro F
authors.initials: PF
authors.lastname: Marrero
authors.forename: Joan C
authors.initials: JC
authors.lastname: Rodríguez
mesh_terms: D000426:Alcohol Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D000438:Alcohols / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D002635:Chenodeoxycholic Acid / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D008024:Ligands; D008297:Male; D051379:Mice; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics; D020218:Response Elements / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000426:Alcohol Dehydrogenase; D000438:Alcohols; D002635:Chenodeoxycholic Acid; D007555:Isoxazoles; D008024:Ligands; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C489332:ADH1B protein, human; C412815:GW 4064
keywords: ethanol; farnesoid X receptor; gene regulation; liver metabolism