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Author Notes:

Correspondence: Shanthi Srinivasan, MD, Emory University School of Medicine, Division of Digestive Diseases, 615 Michael St, Suite 201, Atlanta, GA 30322. Phone: 404-727-7127; Fax: 404-727-5767; ssrini2@emory.edu

Subjects:

Research Funding:

This work is supported by U.S. National Institutes of Health (NIH) grants R01DK080684 (Shanthi Srinivasan) and R01DK044234 and R01AA022601 (Mark Czaja), and VA Research and Development Merit Review Award # BX000136-08 (Shanthi Srinivasan).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Gastroenterology & Hepatology
  • Fatty liver disease
  • Mammalian target
  • Mitochondrial dysfunction
  • Hepatic steatosis
  • Oxidative stress
  • Metabolism
  • Rapamycin
  • Promotes
  • Insulin
  • Gastroenterology

Glial Cell Line-Derived Neurotrophic Factor Enhances Autophagic Flux in Mouse and Rat Hepatocytes and Protects Against Palmitate Lipotoxicity

Tools:

Journal Title:

Hepatology

Volume:

Volume 69, Number 6

Publisher:

, Pages 2455-2470

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Glial cell line–derived neurotrophic factor (GDNF) is a protein that is required for the development and survival of enteric, sympathetic, and catecholaminergic neurons. We previously reported that GDNF is protective against high fat diet (HFD)-induced hepatic steatosis in mice through suppression of hepatic expression of peroxisome proliferator activated receptor-γ and genes encoding enzymes involved in de novo lipogenesis. We also reported that transgenic overexpression of GDNF in mice prevented the HFD-induced liver accumulation of the autophagy cargo-associated protein p62/sequestosome 1 characteristic of impaired autophagy. Here we investigated the effects of GDNF on hepatic autophagy in response to increased fat load, and on hepatocyte mitochondrial fatty acid β-oxidation and cell survival. GDNF not only prevented the reductions in the liver levels of some key autophagy-related proteins, including Atg5, Atg7, Beclin-1 and LC3A/B-II, seen in HFD-fed control mice, but enhanced their levels after 12 weeks of HFD feeding. In vitro, GDNF accelerated autophagic cargo clearance in primary mouse hepatocytes and a rat hepatocyte cell line, and reduced the phosphorylation of the mechanistic target of rapamycin complex downstream-target p70S6 kinase similar to the autophagy activator rapamycin. GDNF also enhanced mitochondrial fatty acid β-oxidation in primary mouse and rat hepatocytes, and protected against palmitate-induced lipotoxicity. Conclusion: We demonstrate a role for GDNF in enhancing hepatic autophagy and in potentiating mitochondrial function and fatty acid oxidation. Our studies show that GDNF and its receptor agonists could be useful for enhancing hepatocyte survival and protecting against fatty acid–induced hepatic lipotoxicity.

Copyright information:

© 2019 by the American Association for the Study of Liver Diseases.

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