Document Detail


Fatty acids suppress autophagic turnover in β-cells.
MedLine Citation:
PMID:  21859708     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Recent studies have shown that autophagy is essential for proper β-cell function and survival. However, it is yet unclear under what pathogenic conditions autophagy is inhibited in β-cells. Here, we report that long term exposure to fatty acids and glucose block autophagic flux in β-cells, contributing to their toxic effect. INS1 cells expressing GFP-LC3 (an autophagosome marker) were treated with 0.4 mm palmitate, 0.4 mm oleate, and various concentrations of glucose for 22 h. Kinetics of the effect of fatty acids on autophagy showed a biphasic response. During the second phase of autophagy, the size of autophagosomes and the content of autophagosome substrates (GFP-LC3, p62) and endogenous LC3 was increased. During the same phase, fatty acids suppressed autophagic degradation of long lived protein in both INS1 cells and islets. In INS1 cells, palmitate induced a 3-fold decrease in the number and the acidity of Acidic Vesicular Organelles. This decrease was associated with a suppression of hydrolase activity, suppression of endocytosis, and suppression of oxidative phosphorylation. The combination of fatty acids with glucose synergistically suppressed autophagic turnover, concomitantly suppressing insulin secretion. Rapamycin treatment resulted in partial reversal of the inhibition of autophagic flux, the inhibition of insulin secretion, and the increase in cell death. Our results indicate that excess nutrient could impair autophagy in the long term, hence contributing to nutrient-induced β-cell dysfunction. This may provide a novel mechanism that connects diet-induced obesity and diabetes.
Authors:
Guy Las; Sam B Serada; Jakob D Wikstrom; Gilad Twig; Orian S Shirihai
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-08-21
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  286     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2011 Dec 
Date Detail:
Created Date:  2011-12-05     Completed Date:  2012-02-21     Revised Date:  2013-06-27    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  42534-44     Citation Subset:  IM    
Affiliation:
Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Autophagy
Cell Line
Cell Separation
Diabetes Mellitus / metabolism
Fatty Acids / metabolism*
Flow Cytometry
Glucose / metabolism
Green Fluorescent Proteins / metabolism
Insulin / metabolism
Insulin-Secreting Cells / metabolism*
Lysosomes / metabolism
Male
Membrane Potentials
Mice
Mice, Inbred C57BL
Mitochondria / metabolism
Sirolimus / pharmacology
Grant Support
ID/Acronym/Agency:
DK035914/DK/NIDDK NIH HHS; R01 DK074778/DK/NIDDK NIH HHS; R01 HL071629-03/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Fatty Acids; 0/Insulin; 147336-22-9/Green Fluorescent Proteins; 50-99-7/Glucose; 53123-88-9/Sirolimus
Comments/Corrections

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


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