title: Retinoid regulation of antiviral innate immunity in hepatocytes.
abstract: Persistent infection of hepatitis C virus (HCV) is one of the leading causes of end-stage liver disease (ESLD), such as decompensated cirrhosis and liver cancer. Of particular note, nearly half of HCV-infected people in the United States are reported to be heavy drinkers. This particular group of patients is known to rapidly progress to the ESLD. Although accelerated disease progression among alcohol abusers infected with HCV is clinically well recognized, the molecular pathophysiology behind this manifestation has not been well elucidated. Hepatocytes metabolize ethanol (EtOH) primarily through two steps of oxidative catabolism in which alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) play central roles. The ADH-ALDH pathway also governs the metabolism of retinol (vitamin A) to its transcriptionally active metabolite, retinoic acid (RA). In this study, we defined that the ADH-ALDH pathway serves as a potent antiviral host factor in hepatocytes, which regulates the expression of interferon (IFN)-stimulated genes (ISGs) by biogenesis of RA. ISGs constitute over 300 antiviral effectors, which cooperatively govern intracellular antiviral innate immunity. Our study revealed that intracellular RA levels greatly influence ISG expression under basal conditions. Moreover, RA augments ISG induction in response to viral infection or exposure to IFN in a gene-specific manner. Lastly, our results demonstrated that EtOH attenuates the antiviral function of the ADH-ALDH pathway, which suggests the possibility that EtOH-retinol metabolic competition is one of the molecular mechanisms for the synergism between HCV and alcohol abuse in liver disease progression.
  
  
  
  RA plays a critical role in the regulation of intracellular antiviral innate immunity in hepatocytes. (Hepatology 2016;63:1783-1795).
authors.affiliation: Department of Medicine, USC Research Center for Liver Diseases, Division of Gastrointestinal and Liver Diseases, University of Southern California, Los Angeles, CA.
authors.forename: Noell E
authors.initials: NE
authors.lastname: Cho
authors.affiliation: Department of Medicine, USC Research Center for Liver Diseases, Division of Gastrointestinal and Liver Diseases, University of Southern California, Los Angeles, CA.
authors.forename: Bo-Ram
authors.initials: BR
authors.lastname: Bang
authors.affiliation: Department of Medicine, USC Research Center for Liver Diseases, Division of Gastrointestinal and Liver Diseases, University of Southern California, Los Angeles, CA.
authors.forename: Purnima
authors.initials: P
authors.lastname: Gurung
authors.affiliation: Bioinformatics Service, Norris Medical Library, University of Southern California, Los Angeles, CA.
authors.forename: Meng
authors.initials: M
authors.lastname: Li
authors.affiliation: Veterans Administration Medical Center and Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE.
authors.forename: Dahn L
authors.initials: DL
authors.lastname: Clemens
authors.affiliation: Department of Cellular and Physiological Sciences, Biomedical Research Center, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: T Michael
authors.initials: TM
authors.lastname: Underhill
authors.affiliation: Department of Pediatrics, University of Arkansas for Medical Sciences, and Arkansas Children's Hospital Research Institute, Little Rock, AR.
authors.forename: Laura P
authors.initials: LP
authors.lastname: James
authors.affiliation: Department of Biology, Northwest Nazarene University, Nampa, ID.
authors.forename: Jenifer R
authors.initials: JR
authors.lastname: Chase
authors.affiliation: Department of Medicine, USC Research Center for Liver Diseases, Division of Gastrointestinal and Liver Diseases, University of Southern California, Los Angeles, CA.|Southern California Research Center for ALPD and Cirrhosis, Los Angeles, CA.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Saito
mesh_terms: D000818:Animals; D002460:Cell Line; D000431:Ethanol / Q000009:adverse effects / Q000378:metabolism; D005786:Gene Expression Regulation; D019698:Hepatitis C, Chronic / Q000150:complications; D022781:Hepatocytes / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D008108:Liver Diseases, Alcoholic / Q000150:complications; D017093:Liver Failure / Q000209:etiology*; D008810:Mice, Inbred C57BL; D014801:Vitamin A / Q000378:metabolism*
chemical_list: D014801:Vitamin A; D000431:Ethanol