title: Glial cell line-derived neurotrophic factor protects against high-fat diet-induced hepatic steatosis by suppressing hepatic PPAR-γ expression.
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 HFD-induced 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.
authors.affiliation: Division of Digestive Diseases, Emory University School of Medicine, Atlanta, Georgia; Atlanta Veterans Affairs Medical Center, Decatur, Georgia;
authors.forename: Simon Musyoka
authors.initials: SM
authors.lastname: Mwangi
authors.affiliation: Division of Digestive Diseases, Emory University School of Medicine, Atlanta, Georgia;
authors.forename: Sophia
authors.initials: S
authors.lastname: Peng
authors.affiliation: Division of Digestive Diseases, Emory University School of Medicine, Atlanta, Georgia; Atlanta Veterans Affairs Medical Center, Decatur, Georgia;
authors.forename: Behtash Ghazi
authors.initials: BG
authors.lastname: Nezami
authors.affiliation: Division of Digestive Diseases, Emory University School of Medicine, Atlanta, Georgia; Atlanta Veterans Affairs Medical Center, Decatur, Georgia;
authors.forename: Natalie
authors.initials: N
authors.lastname: Thorn
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia;
authors.forename: Alton B
authors.initials: AB
authors.lastname: Farris
authors.affiliation: Internal Medicine (Renal Division), Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Jain
authors.affiliation: Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia; and.
authors.forename: Hamed
authors.initials: H
authors.lastname: Laroui
authors.affiliation: Atlanta Veterans Affairs Medical Center, Decatur, Georgia; Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia; and.
authors.forename: Didier
authors.initials: D
authors.lastname: Merlin
authors.affiliation: Division of Digestive Diseases, Emory University School of Medicine, Atlanta, Georgia; Atlanta Veterans Affairs Medical Center, Decatur, Georgia;
authors.forename: Frank
authors.initials: F
authors.lastname: Anania
authors.affiliation: Division of Digestive Diseases, Emory University School of Medicine, Atlanta, Georgia; Atlanta Veterans Affairs Medical Center, Decatur, Georgia; ssrini2@emory.edu.
authors.forename: Shanthi
authors.initials: S
authors.lastname: Srinivasan
mesh_terms: D000818:Animals; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat; D005234:Fatty Liver / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D053758:Nanoparticles / Q000008:administration & dosage / Q000627:therapeutic use; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014280:Triglycerides / Q000378:metabolism
chemical_list: D018955:CD36 Antigens; D051100:Glial Cell Line-Derived Neurotrophic Factor; D047495:PPAR gamma; D014280:Triglycerides
keywords: de novo lipogenesis; nanoparticles; nonalcoholic fatty liver disease; peroxisome proliferator-activated receptor-γ; transgenic