Retinoid regulation of antiviral innate immunity in hepatocytes

Noell E. Cho, Bo Ram Bang, Purnima Gurung, Meng Li, Dahn L Clemens, T. Michael Underhill, Laura P. James, Jenifer R. Chase, Takeshi Saito

Research output: Contribution to journalArticle

8 Citations (Scopus)

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. Conclusions: RA plays a critical role in the regulation of intracellular antiviral innate immunity in hepatocytes. (Hepatology 2016;63:1783-1795).

Original languageEnglish (US)
Pages (from-to)1783-1795
Number of pages13
JournalHepatology
Volume63
Issue number6
DOIs
StatePublished - Jan 1 2016

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Retinoids
Tretinoin
Aldehyde Dehydrogenase
Innate Immunity
Alcohol Dehydrogenase
Antiviral Agents
Hepatocytes
Hepacivirus
Vitamin A
End Stage Liver Disease
Interferons
Genes
Disease Progression
Gastroenterology
Virus Diseases
Liver Neoplasms
Alcoholism
Liver Diseases
Fibrosis
Ethanol

ASJC Scopus subject areas

  • Hepatology

Cite this

Cho, N. E., Bang, B. R., Gurung, P., Li, M., Clemens, D. L., Underhill, T. M., ... Saito, T. (2016). Retinoid regulation of antiviral innate immunity in hepatocytes. Hepatology, 63(6), 1783-1795. https://doi.org/10.1002/hep.28380

Retinoid regulation of antiviral innate immunity in hepatocytes. / Cho, Noell E.; Bang, Bo Ram; Gurung, Purnima; Li, Meng; Clemens, Dahn L; Underhill, T. Michael; James, Laura P.; Chase, Jenifer R.; Saito, Takeshi.

In: Hepatology, Vol. 63, No. 6, 01.01.2016, p. 1783-1795.

Research output: Contribution to journalArticle

Cho, NE, Bang, BR, Gurung, P, Li, M, Clemens, DL, Underhill, TM, James, LP, Chase, JR & Saito, T 2016, 'Retinoid regulation of antiviral innate immunity in hepatocytes', Hepatology, vol. 63, no. 6, pp. 1783-1795. https://doi.org/10.1002/hep.28380
Cho NE, Bang BR, Gurung P, Li M, Clemens DL, Underhill TM et al. Retinoid regulation of antiviral innate immunity in hepatocytes. Hepatology. 2016 Jan 1;63(6):1783-1795. https://doi.org/10.1002/hep.28380
Cho, Noell E. ; Bang, Bo Ram ; Gurung, Purnima ; Li, Meng ; Clemens, Dahn L ; Underhill, T. Michael ; James, Laura P. ; Chase, Jenifer R. ; Saito, Takeshi. / Retinoid regulation of antiviral innate immunity in hepatocytes. In: Hepatology. 2016 ; Vol. 63, No. 6. pp. 1783-1795.
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