Glial cell line-derived neurotrophic factor protects against high-fat diet-induced hepatic steatosis by suppressing hepatic PPAR-γ expression

Simon Musyoka Mwangi, Sophia Peng, Behtash Ghazi Nezami, Natalie Thorn, Alton B. Farris, Sanjay Jain, Hamed Laroui, Didier Merlin, Frank Anania, Shanthi Srinivasan

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Glial cell line-derived neurotrophic factor (GDNF) protects against high-fat diet (HFD)-induced hepatic steatosis in mice, however, the mechanisms involved are not known. In this study we investigated the effects of GDNF overexpression and nanoparticle delivery of GDNF in mice on hepatic steatosis and fibrosis and the expression of genes involved in the regulation of hepatic lipid uptake and de novo lipogenesis. Transgenic overexpression of GDNF in liver and other metabolically active tissues was protective against HFD-induced hepatic steatosis. Mice overexpressing GDNF had significantly reduced P62/sequestosome 1 protein levels suggestive of accelerated autophagic clearance. They also had significantly reduced peroxisome proliferator-activated receptor-γ (PPAR-γ) and CD36 gene expression and protein levels, and lower expression of mRNA coding for enzymes involved in de novo lipogenesis. GDNF-loaded nanoparticles were protective against short-term HFD-induced hepatic steatosis and attenuated liver fibrosis in mice with long-standing HFDinduced hepatic steatosis. They also suppressed the liver expression of steatosis-associated genes. In vitro, GDNF suppressed triglyceride accumulation in Hep G2 cells through enhanced p38 mitogen-activated protein kinase-dependent signaling and inhibition of PPAR-γ gene promoter activity. These results show that GDNF acts directly in the liver to protect against HFD-induced cellular stress and that GDNF may have a role in the treatment of nonalcoholic fatty liver disease.

Original languageEnglish
Pages (from-to)G103-G116
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume310
Issue number2
DOIs
StatePublished - 2016

Keywords

  • De novo lipogenesis
  • Nanoparticles
  • Nonalcoholic fatty liver disease
  • Peroxisome proliferator-activated receptor-γ
  • Transgenic

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