Department of Legal Medicine, Kanagawa Dental University, 82 Inaokacho, Yokosuka 238-8580, Japan.
Department of Legal Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan.
Int J Mol Sci. 2023 Jul 28;24(15):12102. doi: 10.3390/ijms241512102.
Lipid accumulation in the liver due to chronic alcohol consumption (CAC) is crucial in the development of alcohol liver disease (ALD). It is promoted by the NADH/NAD ratio increase via alcohol dehydrogenase (ADH)-dependent alcohol metabolism and lipogenesis increase via peroxisome proliferator-activated receptor γ (PPARγ) in the liver. The transcriptional activity of PPARγ on lipogenic genes is inhibited by S-nitrosylation but activated by denitrosylation via S-nitrosoglutathione reductase (GSNOR), an enzyme identical to ADH3. Besides ADH1, ADH3 also participates in alcohol metabolism. Therefore, we investigated the specific contribution of ADH3 to ALD onset. ADH3-knockout () and wild-type (WT) mice were administered a 10% ethanol solution for 12 months. exhibited no significant pathological changes in the liver, whereas WT exhibited marked hepatic lipid accumulation ( < 0.005) with increased serum transaminase levels. exhibited no death during CAC, whereas WT exhibited a 40% death. Liver mRNA levels were elevated by CAC in WT ( < 0.01). The alcohol elimination rate measured after injecting 4 g/kg ethanol was not significantly different between two strains, although the rate was increased in both strains by CAC. Thus, ADH3 plays a key role in the ALD onset, likely by acting as GSNOR.
由于慢性酒精摄入导致的肝脏脂质积累（CAC）在酒精性肝病（ALD）的发展中至关重要。这种积累是通过酒精脱氢酶（ADH）依赖性酒精代谢导致 NADH/NAD 比例增加，以及通过肝脏中的过氧化物酶体增殖物激活受体γ（PPARγ）促进脂肪生成增加而导致的。PPARγ 对脂肪生成基因的转录活性受到 S-亚硝基化的抑制，但通过 S-亚硝基谷胱甘肽还原酶（GSNOR）的去硝基化而被激活，GSNOR 与 ADH3 是同一种酶。除了 ADH1，ADH3 也参与酒精代谢。因此，我们研究了 ADH3 对 ALD 发病的具体贡献。ADH3 敲除（）和野生型（WT）小鼠给予 10%乙醇溶液 12 个月。与 WT 相比，没有观察到肝脏的明显病理变化（<0.005），而 WT 表现出明显的肝脂质积累，血清转氨酶水平升高。在 CAC 过程中，没有观察到 WT 的死亡（<0.005），而 WT 表现出 40%的死亡。WT 中的 CAC 导致肝 mRNA 水平升高（<0.01）。在两种品系中，注射 4 g/kg 乙醇后测量的酒精消除率没有显著差异，尽管 CAC 增加了两种品系的消除率。因此，ADH3 在 ALD 的发病中起关键作用，可能通过作为 GSNOR 发挥作用。
