Glial cell derived neurotrophic factor prevents western diet and palmitate-induced hepatocyte oxidative damage and death through SIRT3

• Type of Material: Article
• Authors: Simon Mwangi, Emory University; Ge Li, Emory University; Arun Balasubramaniam, Emory University; Didier Merlin, Atlanta VA Health Care System; Paul Dawson, Emory University; Young Jang, Emory University; Michael C Hart, Atlanta VA Health Care System; Mark Czaja, Emory University; Shanthi Srinivasan, Emory University
• Language: English
• Date: 2022-12-01
• Publisher: Springer Nature Limited
• Publication Version: Final Published Version
• Copyright Statement: © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2022
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41598-022-20101-1
• Title of Journal or Parent Work: Scientific Reports
• Volume: 12
• Issue: 1
• Start Page: 15838
• End Page: 15838
• Keywords: Hepatocytes; Glial Cell Line-Derived Neurotrophic Factor; Oxidative Stress; Palmitates; Diet, Western; Non-alcoholic Fatty Liver Disease; Mice; Mice, Transgenic; Diet, High-Fat; Sirtuin 3; Animals; Superoxide Dismutase
• Research Categories: Health Sciences, Nutrition

Abstract

Nonalcoholic fatty liver disease (NAFLD) is associated with increased oxidative stress that leads to hepatocyte and mitochondrial damage. In this study we investigated the mechanisms involved in the induction of oxidative stress and impairment of mitochondrial quality control and mitophagy in hepatocytes by the saturated fatty acid palmitate and Western diet feeding in mice and if their harmful effects could be reversed by the neurotrophic factor glial cell derived neurotrophic factor (GDNF). Western diet (WD)-feeding increased hepatic lipid peroxidation in control mice and, in vitro palmitate induced oxidative stress and impaired the mitophagic clearance of damaged mitochondria in hepatocytes. This was accompanied by reductions in hepatocyte sirtuin 3 (SIRT3) deacetylase activity, gene expression and protein levels as well as in superoxide dismutase enzyme activity. These reductions were reversed in the liver of Western diet fed GDNF transgenic mice and in hepatocytes exposed to palmitate in the presence of GDNF. We demonstrate an important role for Western diet and palmitate in inducing oxidative stress and impairing mitophagy in hepatocytes and an ability of GDNF to prevent this. These findings suggest that GDNF or its agonists may be a potential therapy for the prevention or treatment of NAFLD.