| 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 |
Related Documents
:
|
6768756 - Regulation of amino acid transport in chicken embryo fibroblasts by purified multiplica... 1347456 - Transport of l-glutamic acid in the fission yeast schizosaccharomyces pombe. 12650826 - Interaction of human and rat organic anion transporter 2 with various cephalosporin ant... 7085766 - Effects of cycloheximide and actinomycin d on the amino acid transport system of tetrah... 10731526 - The rate at which human sperm are immobilized and killed by mild acidity. 17496206 - Kinetics of valproic acid glucuronidation: evidence for in vivo autoactivation. |
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: 2012-04-27 |
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. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| 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
Previous Document: Completeness and changes in registered data and reporting bias of randomized controlled trials in IC...
Next Document: Hepcidin is involved in iron regulation in the ischemic brain.