Document Detail


Selective hepatic insulin resistance in a murine model heterozygous for a mitochondrial trifunctional protein defect.
MedLine Citation:
PMID:  23359250     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Earlier reports suggest a link between mitochondrial dysfunction and development of hepatic insulin resistance. Here we used a murine model heterozygous (HET) for a mitochondrial trifunctional protein (MTP) gene defect to determine if a primary defect in mitochondrial long-chain fatty acid oxidation disrupts hepatic insulin action. Hyperinsulinemic-euglycemic clamps and signaling studies were performed for assessment of whole-body and hepatic insulin resistance/signaling. In addition, hepatic fatty acid oxidation and hepatic insulin action were assessed in vitro using primary hepatocytes isolated from HET and wildtype (WT) mice. In both hepatic mitochondria and isolated primary hepatocytes, heterozygosity of MTP caused an ∼50% reduction in mitochondrial fatty acid oxidation, a significantly impaired glucose disposal during the insulin clamp, and a markedly lower insulin-stimulated suppression of hepatic glucose production. HET mice also exhibited impaired insulin signaling, with increased hepatic phosphorylation of IRS2 (ser731) and reduced Akt phosphorylation (ser473) in both hepatic tissue and isolated primary hepatocytes. Assessment of insulin-stimulated FOXO1/phospho-FOXO1 protein content and PEPCK/G6Pase messenger RNA (mRNA) expression did not reveal differences between HET and WT mice. However, insulin-induced phosphorylation of GSK3β was significantly blunted in HET mice. Hepatic insulin resistance was associated with an increased methylation status of the catalytic subunit of protein phosphatase 2A (PP2A-C), but was not associated with differences in hepatic diacylglycerol content, activated protein kinase C-ϵ (PKC-ϵ), inhibitor κB kinase β (IKK-β), c-Jun N-terminal kinase (JNK), or phospho-JNK protein contents. Surprisingly, hepatic ceramides were significantly lower in the HET mice compared with WT. Conclusion: A primary defect in mitochondrial fatty acid β-oxidation causes hepatic insulin resistance selective to hepatic glycogen metabolism that is associated with elevated methylated PP2A-C, but independent of other mechanisms commonly considered responsible for insulin resistance. (HEPATOLOGY 2013;).
Authors:
R Scott Rector; E Matthew Morris; Suzanne Ridenhour; Grace M Meers; Fong-Fu Hsu; John Turk; Jamal A Ibdah
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-04-26
Journal Detail:
Title:  Hepatology (Baltimore, Md.)     Volume:  57     ISSN:  1527-3350     ISO Abbreviation:  Hepatology     Publication Date:  2013 Jun 
Date Detail:
Created Date:  2013-06-13     Completed Date:  2013-08-16     Revised Date:  2014-06-03    
Medline Journal Info:
Nlm Unique ID:  8302946     Medline TA:  Hepatology     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2213-23     Citation Subset:  IM    
Copyright Information:
Copyright © 2013 American Association for the Study of Liver Diseases.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Animals
Disease Models, Animal
Fatty Acids / metabolism
Fatty Liver / genetics,  metabolism*
Glucose Clamp Technique
Heterozygote
Insulin / metabolism
Insulin Resistance*
Lipid Metabolism*
Male
Mice
Mitochondria / metabolism
Mitochondrial Trifunctional Protein
Multienzyme Complexes / genetics*
Oxidation-Reduction
Grant Support
ID/Acronym/Agency:
DK-56345/DK/NIDDK NIH HHS; F32 DK-83182/DK/NIDDK NIH HHS; F32 DK083182/DK/NIDDK NIH HHS; P30 DK056341/DK/NIDDK NIH HHS; P30-DK56341/DK/NIDDK NIH HHS; P41 RR000954/RR/NCRR NIH HHS; P41-RR00954/RR/NCRR NIH HHS; P60 DK020579/DK/NIDDK NIH HHS; P60-DK20579/DK/NIDDK NIH HHS; R01 DK056345/DK/NIDDK NIH HHS; T32 AR 048523-07/AR/NIAMS NIH HHS; T32 AR048523/AR/NIAMS NIH HHS
Chemical
Reg. No./Substance:
0/Fatty Acids; 0/Insulin; 0/Multienzyme Complexes; EC 2.3.1.16/Mitochondrial Trifunctional Protein
Comments/Corrections

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


Previous Document:  Characterizing crystal disorder of trospium chloride: A comprehensive,(13) C CP/MAS NMR, DSC, FTIR, ...
Next Document:  Turkish adaptation of the short form of the pelvic organ Prolapse/Urinary Incontinence Sexual Functi...