Journal Article

GLP-1 Analogs Reduce Hepatocyte Steatosis and Improve Survival by Enhancing the Unfolded Protein Response and Promoting Macroautophagy

Saxena, Neeraj K., Mells, Jamie E., Fu, Ping P., Anania, Frank A., Sharma, Shvetank

2011

Overview

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. 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. 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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adipocytes - drug effects / Adipocytes - pathology / Analogs / Animals / Apoptosis / Apoptosis - drug effects / Autophagy / Autophagy - drug effects / Biology / CCAAT/enhancer-binding protein / Cell death / Cytokines / Diabetes / Diet, High-Fat - adverse effects / Dietary Carbohydrates - adverse effects / Electron microscopy / Endoplasmic reticulum / Endoplasmic Reticulum Stress - drug effects / Fatty acids / Fatty liver / Fatty Liver - drug therapy / Fatty Liver - etiology / Fatty Liver - metabolism / Fatty Liver - pathology / Fructose / Fructose - adverse effects / Genes / GLP-1 receptor agonists / Glucagon-Like Peptide 1 - analogs & derivatives / Growth hormones / Hepatocytes / Hepatocytes - drug effects / Hepatocytes - metabolism / Hepatocytes - pathology / Homology / Humans / Insulin resistance / Kinases / Lesions / Life Style / Lipids / Liver / Liver diseases / Lysates / Male / Medicine / Mice / Mice, Inbred C57BL / Microscopy / Mortality / Obesity - drug therapy / Obesity - etiology / Obesity - metabolism / Obesity - pathology / Oils & fats / Peptides - chemistry / Peptides - pharmacology / Peptides - therapeutic use / Phagocytosis / Prohibition / Protein folding / Proteins / Rodents / Saturated fatty acids / Steatosis / Stress / Stress management / Stresses / Studies / Survival / Survival Analysis / Trans fats / Transmission electron microscopy / Type 2 diabetes / Unfolded Protein Response - drug effects / Unsaturated fatty acids / Venoms - chemistry / Venoms - pharmacology / Venoms - therapeutic use