title: GLP-1 analogs reduce hepatocyte steatosis and improve survival by enhancing the unfolded protein response and promoting macroautophagy.
abstract: BACKGROUND
  Nonalcoholic fatty liver disease (NAFLD) is a known outcome of hepatosteatosis. Free fatty acids (FFA) induce the unfolded protein response (UPR) or endoplasmic reticulum (ER) stress that may induce apoptosis. Recent data indicate ER stress to be a major player in the progression of fatty liver to more aggressive lesions. Autophagy on the other hand has been demonstrated to be protective against ER stress-induced cell death. We hypothesized that exendin-4 (GLP-1 analog) treatment of fat loaded hepatocytes can reduce steatosis by autophagy which leads to reduced ER stress-related hepatocyte apoptosis.
  
  
  RESULTS
  Primary human hepatocytes were loaded with saturated, cis- and trans-unsaturated fatty acids (palmitic, oleic and elaidic acid respectively). Steatosis, induced with all three fatty acids, was significantly resolved after exendin-4 treatment. Exendin-4 sustained levels of GRP78 expression in fat-loaded cells when compared to untreated fat-loaded cells alone. In contrast, CHOP (C/EBP homologous protein); the penultimate protein that leads to ER stress-related cell death was significantly decreased by exendin-4 in hepatocytes loaded with fatty acids. Finally, exendin-4 in fat loaded hepatocytes clearly promoted gene products associated with macroautophagy as measured by enhanced production of both Beclin-1 and LC3B-II, markers for autophagy; and visualized by transmission electron microscopy (TEM). Similar observations were made in mouse liver lysates after mice were fed with high fat high fructose diet and treated with a long acting GLP-1 receptor agonist, liraglutide.
  
  
  CONCLUSIONS
  GLP-1 proteins appear to protect hepatocytes from fatty acid-related death by prohibition of a dysfunctional ER stress response; and reduce fatty acid accumulation, by activation of both macro-and chaperone-mediated autophagy. These findings provide a novel role for GLP-1 proteins in halting the progression of more aggressive lesions from underlying steatosis in humans afflicted with NAFLD.
authors.affiliation: Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Shvetank
authors.initials: S
authors.lastname: Sharma
authors.forename: Jamie E
authors.initials: JE
authors.lastname: Mells
authors.forename: Ping P
authors.initials: PP
authors.lastname: Fu
authors.forename: Neeraj K
authors.initials: NK
authors.lastname: Saxena
authors.forename: Frank A
authors.initials: FA
authors.lastname: Anania
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D059305:Diet, High-Fat / Q000009:adverse effects; D004040:Dietary Carbohydrates / Q000009:adverse effects; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D000077270:Exenatide; D005234:Fatty Liver / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D005632:Fructose / Q000009:adverse effects; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008019:Life Style; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D016019:Survival Analysis; D056811:Unfolded Protein Response / Q000187:drug effects*; D014688:Venoms / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D004040:Dietary Carbohydrates; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D010455:Peptides; D014688:Venoms; D005632:Fructose; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide