Alcohol dehydrogenase 3 contributes to the protection of liver from nonalcoholic steatohepatitis.

Abstract

Nutritional steatohepatitis is closely associated with dysregulation of lipid metabolism and oxidative stress control. ADH3 is a highly conserved bifunctional enzyme involved in formaldehyde detoxification and termination of nitric oxide signaling. Formaldehyde and nitric oxide are nonenzymatically conjugated with glutathione, which is regenerated after ADH3 metabolizes the conjugates. To clarify roles of ADH3 in nutritional liver diseases, we placed Adh3-null mice on a methionine- and choline-deficient (MCD) diet. The Adh3-null mice developed steatohepatitis more rapidly than wild-type mice, indicating that ADH3 protects liver from nutritional steatohepatitis. NRF2, which is a key regulator of cytoprotective genes against oxidative stress, was activated in the Adh3-null mice with liver damage. In the absence of NRF2, the Adh3 disruption caused severe steatohepatitis by the MCD diet feeding accompanied by significant decrease in glutathione, suggesting cooperative function between ADH3 and NRF2 in the maintenance of cellular glutathione level for cytoprotection. Conversely, with enhanced NRF2 activity, the Adh3 disruption did not cause steatohepatitis but induced steatosis, suggesting that perturbation of lipid metabolism in ADH3-deficiency is not compensated by NRF2. Thus, ADH3 protects liver from steatosis by supporting normal lipid metabolism and prevents progression of steatosis into steatohepatitis by maintaining the cellular glutathione level.

• Authors: Maki Goto, Hiroshi Kitamura, Md Morshedul Alam, Nao Ota, Takeshi Haseba, Toshio Akimoto, Akio Shimizu, Teruko Takano-Yamamoto, Masayuki Yamamoto, Hozumi Motohashi
• Journal: Genes to cells : devoted to molecular & cellular mechanisms (Genes Cells) Vol. 20 Issue 6 Pg. 464-80 (Jun 2015) ISSN: 1365-2443 [Electronic] England
• PMID: 25777368 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 The Molecular Biology Society of Japan and Wiley Publishing Asia Pty Ltd.

Chemical References

• NF-E2-Related Factor 2
• Nfe2l2 protein, mouse
• Methionine
• Adh5 protein, mouse
• Alcohol Dehydrogenase
• Glutathione

Topics

• Alcohol Dehydrogenase (genetics, metabolism)
• Animals
• Choline Deficiency
• Diet
• Disease Progression
• Fatty Liver (metabolism)
• Glutathione (metabolism)
• Lipid Metabolism
• Liver (metabolism, pathology)
• Methionine (deficiency)
• Mice, Inbred C57BL
• Mice, Knockout
• NF-E2-Related Factor 2 (metabolism)
• Non-alcoholic Fatty Liver Disease (prevention & control)