Role of Mesencephalic Astrocyte-Derived Neurotrophic Factor in Alcohol-Induced Liver Injury.

Goma Chhetri,Tongcui Jiang,Xiaofang Tao,Dan Han,Juntang Shao,Yi Yang,Yujun Shen,Yuxian Shen,Yanyan Liang,Peng Wang,Chao Hou,Lijie Feng

doi:10.1155/2020/9034864

Abstract

Consumption of alcohol in immoderate quantity induces endoplasmic reticulum (ER) stress response (alcohol-induced ER stress). Mesencephalic astrocyte-derived neurotrophic factor (MANF), an ER stress-inducible protein, works as an evolutionarily conserved regulator of systemic and liver metabolic homeostasis. In this study, the effects of MANF on alcohol-induced liver injury were explored by using hepatocyte-specific MANF-knockout mice (MANFΔHep) in a chronic-plus-binge alcohol feeding model. We found that alcohol feeding upregulated MANF expression and MANFΔHep mice exhibited more severe liver injury with extra activated ER stress after alcohol feeding. In addition, we found that MANF deficiency activated iNOS and p65 and increased the production of NO and anti-inflammatory cytokines, which was further enhanced after alcohol treatment. Meanwhile, MANF deletion upregulated the levels of CYP2E1, 4-HNE, and MDA and downregulated the levels of GSH and SOD. These results indicate that MANF has potential protection on alcohol-induced liver injury, and the underlying mechanisms may be associated with meliorating the overactivated ER stress triggered by inflammation and oxidative stress via inhibiting and reducing NO/NF-κB and CYP2E1/ROS, respectively. Therefore, MANF might be a negative regulator in alcohol-induced ER stress and participate in the crosstalk between the NF-κB pathway and oxidative stress in the liver. Conclusions. This study identifies a specific role of MANF in alcohol-induced liver injury, which may provide a new approach for the treatment of ALI.

Highlights

Alcoholic liver disease (ALD) is one of the global health issues and has received growing attention
To examine whether alcoholinduced liver injury influences the hepatic expression of Mesencephalic astrocyte-derived neurotrophic factor (MANF), we detected the levels of MANF protein and mRNA in the liver tissues from the model mice
These findings indicate that MANF deletion promotes cytochrome P450 2E1 (CYP2E1) activation and reactive oxygen species (ROS) production in alcohol-induced liver injury, which suggests that MANF may reduce oxidative stress induced by ethanol in the liver

Summary

Introduction

Alcoholic liver disease (ALD) is one of the global health issues and has received growing attention. Ethanol-induced liver injury is largely influenced by drinking patterns, dietary options, and obesity, as well as by environmental factors [1]. ALD is composed of various forms of liver lesions, including hepatic steatosis, fibrosis, and cirrhosis. Alcohol induces liver injury through several mechanisms, including inflammation, oxidative stress, and ER stress [5]. Hepatic biotransformation of ethanol into acetaldehyde mainly involves alcohol dehydrogenase (ALH) and cytochrome P450 2E1 (CYP2E1). Both oxidative metabolic pathways of ethanol lead to the production of reactive oxygen species (ROS). ROS could be removed efficiently by an endogenous protective system, including superoxide dismutase (SOD) and antioxidant GSH [6]. ROS triggers inflammatory responses and cytokine production, which mediate

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Conclusion