| Mitochondrial dysfunction precedes insulin resistance and hepatic steatosis and contributes to the natural history of non-alcoholic fatty liver disease in an obese rodent model. | |
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MedLine Citation:
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PMID: 20347174 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND & AIMS: In this study, we sought to determine the temporal relationship between hepatic mitochondrial dysfunction, hepatic steatosis and insulin resistance, and to examine their potential role in the natural progression of non-alcoholic fatty liver disease (NAFLD) utilising a sedentary, hyperphagic, obese, Otsuka Long-Evans Tokushima Fatty (OLETF) rat model. METHODS: OLETF rats and their non-hyperphagic control Long-Evans Tokushima Otsuka (LETO) rats were sacrificed at 5, 8, 13, 20, and 40 weeks of age (n=6-8 per group). RESULTS: At 5 weeks of age, serum insulin and glucose and hepatic triglyceride (TG) concentrations did not differ between animal groups; however, OLETF animals displayed significant (p<0.01) hepatic mitochondrial dysfunction as measured by reduced hepatic carnitine palmitoyl-CoA transferase-1 activity, fatty acid oxidation, and cytochrome c protein content compared with LETO rats. Hepatic TG levels were significantly elevated by 8 weeks of age, and insulin resistance developed by 13 weeks in the OLETF rats. NAFLD progressively worsened to include hepatocyte ballooning, perivenular fibrosis, 2.5-fold increase in serum ALT, hepatic mitochondrial ultrastructural abnormalities, and increased hepatic oxidative stress in the OLETF animals at later ages. Measures of hepatic mitochondrial content and function including beta-hydroxyacyl-CoA dehydrogenase activity, citrate synthase activity, and immunofluorescence staining for mitochondrial carbamoyl phosphate synthetase-1, progressively worsened and were significantly reduced at 40 weeks in OLETF rats compared to LETO animals. CONCLUSIONS: Our study documents that hepatic mitochondrial dysfunction precedes the development of NAFLD and insulin resistance in the OLETF rats. This evidence suggests that progressive mitochondrial dysfunction contributes to the natural history of obesity-associated NAFLD. |
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Authors:
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R Scott Rector; John P Thyfault; Grace M Uptergrove; E Matthew Morris; Scott P Naples; Sarah J Borengasser; Catherine R Mikus; Matthew J Laye; M Harold Laughlin; Frank W Booth; Jamal A Ibdah |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-03-04 |
Journal Detail:
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Title: Journal of hepatology Volume: 52 ISSN: 0168-8278 ISO Abbreviation: J. Hepatol. Publication Date: 2010 May |
Date Detail:
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Created Date: 2010-05-03 Completed Date: 2010-08-10 Revised Date: 2011-07-28 |
Medline Journal Info:
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Nlm Unique ID: 8503886 Medline TA: J Hepatol Country: England |
Other Details:
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Languages: eng Pagination: 727-36 Citation Subset: IM |
Copyright Information:
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Copyright (c) 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. |
Affiliation:
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Division of Gastroenterology and Hepatology, 5 Hospital Drive, CE405 Clinical Support & Education Building, University of Missouri-Columbia, Columbia, MO 65212, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adipose Tissue
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physiopathology Animals Azo Compounds Body Composition Disease Models, Animal Energy Intake Fatty Liver / physiopathology* Glutathione / metabolism Glutathione Disulfide / metabolism Insulin Resistance / physiology* Male Mitochondria, Liver / physiology, ultrastructure Obesity / physiopathology* Oxidation-Reduction Palmitic Acid / metabolism Rats Rats, Long-Evans Reference Values Superoxide Dismutase / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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F32 DK-83182/DK/NIDDK NIH HHS; F32 DK083182-02/DK/NIDDK NIH HHS; HL-36088/HL/NHLBI NIH HHS; R01 HL036088-24/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Azo Compounds; 1320-06-5/oil red O; 27025-41-8/Glutathione Disulfide; 57-10-3/Palmitic Acid; 70-18-8/Glutathione; EC 1.15.1.1/Superoxide Dismutase |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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