Document Detail


GLP-1 analogs reduce hepatocyte steatosis and improve survival by enhancing the unfolded protein response and promoting macroautophagy.
MedLine Citation:
PMID:  21957486     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Shvetank Sharma; Jamie E Mells; Ping P Fu; Neeraj K Saxena; Frank A Anania
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2011-09-21
Journal Detail:
Title:  PloS one     Volume:  6     ISSN:  1932-6203     ISO Abbreviation:  PLoS ONE     Publication Date:  2011  
Date Detail:
Created Date:  2011-09-29     Completed Date:  2012-02-03     Revised Date:  2013-06-27    
Medline Journal Info:
Nlm Unique ID:  101285081     Medline TA:  PLoS One     Country:  United States    
Other Details:
Languages:  eng     Pagination:  e25269     Citation Subset:  IM    
Affiliation:
Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America.
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MeSH Terms
Descriptor/Qualifier:
Adipocytes / drug effects,  pathology
Animals
Apoptosis / drug effects
Autophagy / drug effects*
Diet, High-Fat / adverse effects
Dietary Carbohydrates / adverse effects
Endoplasmic Reticulum Stress / drug effects
Fatty Liver / drug therapy*,  etiology,  metabolism,  pathology
Fructose / adverse effects
Glucagon-Like Peptide 1 / analogs & derivatives*
Hepatocytes / drug effects*,  metabolism,  pathology
Humans
Life Style
Male
Mice
Mice, Inbred C57BL
Obesity / drug therapy,  etiology,  metabolism,  pathology
Peptides / chemistry*,  pharmacology*,  therapeutic use
Survival Analysis
Unfolded Protein Response / drug effects*
Venoms / chemistry*,  pharmacology*,  therapeutic use
Grant Support
ID/Acronym/Agency:
K01DK077137/DK/NIDDK NIH HHS; R01DK062092/DK/NIDDK NIH HHS; R01DK075397/DK/NIDDK NIH HHS; R03DK089130/DK/NIDDK NIH HHS; R24DK064399/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Dietary Carbohydrates; 0/Peptides; 0/Venoms; 141732-76-5/exenatide; 30237-26-4/Fructose; 89750-14-1/Glucagon-Like Peptide 1
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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