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Cited by 488Liver Disease Diagnosis and TreatmentMitochondrial Function and PathologyLiver physiology and pathology

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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Rector, R. Scott, Thyfault, John P., Uptergrove, Grace M., Morris, E. Matthew, Naples, Scott P., Borengasser, Sarah J., Mikus, Catherine R., Laye, Matthew J. +3 more·2010·Journal of Hepatology
DOI 10.1016/j.jhep.2009.11.030PMC PMC3070177
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Abstract

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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  • Animal models of mitochondrial dysfunction in NASH have shown alteration in the ETC complexes I, III, and IV.

    “Animal models of mitochondrial dysfunction in NASH have shown alteration in the ETC complexes I, III, and IV [35].”

    From Intervention by picroside II on FFAs induced lipid accumulation and lipotoxicity in HepG2 cells (2021) · cites this paper as [35]

    The Results (page not provided) report mitochondrial dysfunction in OLETF rats, including reduced fatty acid oxidation and cytochrome c content. The Methods’ enzyme activity assays and Results do not identify alterations in ETC complexes I, III, and IV, so the source does not support that specific part of the claim. (LLM, conf=0.85)

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Authors
Rector, R. S., Thyfault, J. P., Uptergrove, G. M., Morris, E. M., Naples, S. P., Borengasser, S. J., Mikus, C. R., Laye, M. J., Laughlin, M. H., Booth, F. W., & Ibdah, J. A.
Affiliations
  • University of Missouri (US)
  • Harry S. Truman Memorial Veterans' Hospital (US)
ORCID
Venue
Journal of Hepatology
Publisher
Elsevier BV
Published
2010-05
Volume
52
Issue
5
Pages
727-736
ISSN
0168-8278 (ISSN-L)
DOI
10.1016/j.jhep.2009.11.030
PMC
PMC3070177
OpenAlex
W2133985126
Cited by
488
References
4
Citations by year
2026: 18 · 2025: 27 · 2024: 40 · 2023: 23 · 2022: 40 · 2021: 30 · 2020: 30 · 2019: 28 · 2018: 36 · 2017: 39 · 2016: 25 · 2015: 34 · 2014: 31 · 2013: 24 · 2012: 32
FWCI
19.84
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Journal of Hepatology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
NIH (HL-36088, F32 DK-83182)
Topics
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Keywords
non-alcoholic fatty liver disease, hepatic mitochondrial dysfunction, insulin resistance, hepatic steatosis, OLETF rats, obesity, fatty acid oxidation, oxidative stress, perivenular fibrosis, hepatocyte ballooning, disease progression
MeSH terms
Adipose Tissue, Animals, Azo Compounds, Body Composition, Energy Intake, Disease Models, Animal, Fatty Liver, Glutathione, Insulin Resistance, Male, Mitochondria, Liver, Obesity, Oxidation-Reduction, Reference Values, Superoxide Dismutase, Palmitic Acid, Glutathione Disulfide, Rats, Long-Evans, Rats

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