Department of Nutrition, University of California Davis, One Shields Ave, Davis, CA, 95616, USA.
Department of Nutrition, University of California Davis, One Shields Ave, Davis, CA, 95616, USA.
Redox Biol. 2020 Sep;36:101658. doi: 10.1016/j.redox.2020.101658. Epub 2020 Jul 24.
Alcoholic liver disease (ALD) is a major health problem and a significant cause of liver-related death. Currently, the mainstay for ALD therapy is alcohol abstinence highlighting the need to develop pharmacotherapeutic approaches. Protein-tyrosine phosphatase 1B (PTP1B) is an established regulator of hepatic functions, but its role in ALD is mostly unexplored. In this study, we used mice with liver-specific PTP1B disruption as well as pharmacological inhibition to investigate the in vivo function of this phosphatase in ALD. We report upregulation of hepatic PTP1B in the chronic plus binge mouse model and, importantly, in liver biopsies of alcoholic hepatitis patients. Also, mice with hepatic PTP1B disruption attenuated ethanol-induced injury, inflammation, and steatosis compared with ethanol-fed control animals. Moreover, PTP1B deficiency was associated with decreased ethanol-induced oxidative stress in vivo and ex vivo. Further, pharmacological modulation of oxidative balance in hepatocytes identified diminished oxidative stress as a contributor to the salutary effects of PTP1B deficiency. Notably, PTP1B pharmacological inhibition elicited beneficial effects and mitigated hepatic injury, inflammation, and steatosis caused by ethanol feeding. In summary, these findings causally link hepatic PTP1B and ALD and define a potential therapeutic target for the management of this disease.
酒精性肝病 (ALD) 是一个主要的健康问题，也是与肝脏相关死亡的主要原因。目前，ALD 治疗的主要方法是戒酒，这突出表明需要开发药物治疗方法。蛋白酪氨酸磷酸酶 1B（PTP1B）是肝脏功能的一种既定调节剂，但它在 ALD 中的作用在很大程度上尚未得到探索。在这项研究中，我们使用肝脏特异性 PTP1B 敲除小鼠以及药理学抑制来研究这种磷酸酶在 ALD 中的体内功能。我们报告了慢性加 binge 小鼠模型中肝 PTP1B 的上调，重要的是，在酒精性肝炎患者的肝活检中也观察到了这种上调。此外，与乙醇喂养的对照动物相比，肝脏 PTP1B 敲除的小鼠减轻了乙醇引起的损伤、炎症和脂肪变性。此外，PTP1B 缺乏与体内和体外乙醇诱导的氧化应激减少有关。此外，肝细胞氧化平衡的药理学调节确定了氧化应激的减少是 PTP1B 缺乏有益作用的原因之一。值得注意的是，PTP1B 的药理学抑制可产生有益的效果，并减轻乙醇喂养引起的肝损伤、炎症和脂肪变性。总之，这些发现将肝 PTP1B 与 ALD 因果关联起来，并为该疾病的管理确定了一个潜在的治疗靶点。
