Hepatic protein tyrosine phosphatase Shp2 disruption mitigates the adverse effects of ethanol in the liver by modulating oxidative stress and ERK signaling

Abstract

AimsChronic excessive alcohol intake is a significant cause of alcohol-associated liver disease (ALD), a leading contributor to liver-related morbidity and mortality. The Src homology phosphatase 2 (Shp2; encoded by Ptpn11) is a widely expressed protein tyrosine phosphatase that modulates hepatic functions, but its role in ALD is mostly uncharted. Main methodsHerein, we explore the effects of liver-specific Shp2 genetic disruption using the established chronic-plus-binge mouse model of ALD. Key findingsWe report that the hepatic Shp2 disruption had beneficial effects and partially ameliorated ethanol-induced injury, inflammation, and steatosis in the liver. Consistently, Shp2 deficiency was associated with decreased ethanol-evoked activation of extracellular signal-regulated kinase (ERK) and oxidative stress in the liver. Moreover, primary hepatocytes with Shp2 deficiency exhibited similar outcomes to those observed upon Shp2 disruption in vivo, including diminished ethanol-induced ERK activation, inflammation, and oxidative stress. Furthermore, pharmacological inhibition of ERK in primary hepatocytes mimicked the effects of Shp2 deficiency and attenuated oxidative stress caused by ethanol. SignificanceCollectively, these findings highlight Shp2 as a modulator of hepatic oxidative stress upon ethanol challenge and suggest the evaluation of this phosphatase as a potential therapeutic target for ALD.