GLP-1 analogs reduce hepatocyte steatosis and improve survival by enhancing the unfolded protein response and promoting macroautophagy

PLoS One. 2011;6(9):e25269. doi: 10.1371/journal.pone.0025269. Epub 2011 Sep 21.

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.

Methodology/principal findings: 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/significance: 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adipocytes / drug effects
  • Adipocytes / pathology
  • Animals
  • Apoptosis / drug effects
  • Autophagy / drug effects*
  • Diet, High-Fat / adverse effects
  • Dietary Carbohydrates / adverse effects
  • Endoplasmic Reticulum Stress / drug effects
  • Exenatide
  • Fatty Liver / drug therapy*
  • Fatty Liver / etiology
  • Fatty Liver / metabolism
  • Fatty Liver / pathology
  • Fructose / adverse effects
  • Glucagon-Like Peptide 1 / analogs & derivatives*
  • Hepatocytes / drug effects*
  • Hepatocytes / metabolism
  • Hepatocytes / pathology
  • Humans
  • Life Style
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Obesity / drug therapy
  • Obesity / etiology
  • Obesity / metabolism
  • Obesity / pathology
  • Peptides / chemistry*
  • Peptides / pharmacology*
  • Peptides / therapeutic use
  • Survival Analysis
  • Unfolded Protein Response / drug effects*
  • Venoms / chemistry*
  • Venoms / pharmacology*
  • Venoms / therapeutic use

Substances

  • Dietary Carbohydrates
  • Peptides
  • Venoms
  • Fructose
  • Glucagon-Like Peptide 1
  • Exenatide