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Mitochondrial dysfunction due to long-chain Acyl-CoA dehydrogenase deficiency causes hepatic steatosis and hepatic insulin resistance
Open accessAbstract
Alterations in mitochondrial function have been implicated in the pathogenesis of insulin resistance and type 2 diabetes. However, it is unclear whether the reduced mitochondrial function is a primary or acquired defect in this process. To determine whether primary defects in mitochondrial β-oxidation can cause insulin resistance, we studied mice with a deficiency of long-chain acyl-CoA dehydrogenase (LCAD), a key enzyme in mitochondrial fatty acid oxidation. Here, we show that LCAD knockout mice develop hepatic steatosis, which is associated with hepatic insulin resistance, as reflected by reduced insulin suppression of hepatic glucose production during a hyperinsulinemic-euglycemic clamp. The defects in insulin action were associated with an ≈40% reduction in insulin-stimulated insulin receptor substrate-2-associated phosphatidylinositol 3-kinase activity and an ≈50% decrease in Akt2 activation. These changes were associated with increased PKCε activity and an aberrant 4-fold increase in diacylglycerol content after insulin stimulation. The increase in diacylglycerol concentration was found to be caused by de novo synthesis of diacylglycerol from medium-chain acyl-CoA after insulin stimulation. These data demonstrate that primary defects in mitochondrial fatty acid oxidation capacity can lead to diacylglycerol accumulation, PKCε activation, and hepatic insulin resistance.
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“Recent studies have shown that increased hepatocellular concentrations of diacylglycerol in nonalcoholic fatty liver disease lead to activation of the protein kinase C epsilon isoform, resulting in reduced insulin signaling and hepatic insulin resistance.23–27”
From Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease (2010) · cites this paper as [27]
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“There is now strong evidence that nonalcoholic fatty liver disease has an important role in causing hepatic insulin resistance.1–3,23–27”
From Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease (2010) · cites this paper as [27]
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Metadata
- Authors
- Zhang, D., Liu, Z.-X., Choi, C. S., Tian, L., Kibbey, R., Dong, J., Cline, G. W., Wood, P. A., & Shulman, G. I.
- Affiliations
- Howard Hughes Medical Institute (US)
- *Howard Hughes Medical Institute and
- Departments of †Internal Medicine and
- University of Alabama at Birmingham (US)
- Corresponding author
- Shulman, Gerald I.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2007-10-23
- Volume
- 104
- Issue
- 43
- Pages
- 17075-17080
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2040460
- OpenAlex
- W2091450162
- Cited by
- 291
- References
- 27
- Citations by year
- 2026: 5 · 2025: 11 · 2024: 10 · 2023: 22 · 2022: 14 · 2021: 11 · 2020: 9 · 2019: 14 · 2018: 13 · 2017: 19 · 2016: 15 · 2015: 19 · 2014: 25 · 2013: 15 · 2012: 22
- FWCI
- 6.76
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Diabetes Association
- U.S. Public Health Service (R01 DK-40936)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01-DK40936, U24DK59635, R01DK040936, U24DK059635)
- National Center for Research Resources (R01-RR02599, R01RR002599)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- long-chain acyl-CoA dehydrogenase deficiency, mitochondrial dysfunction, hepatic steatosis, hepatic insulin resistance, mitochondrial fatty acid oxidation, insulin receptor substrate 2, phosphatidylinositol 3-kinase, AKT2, protein kinase C epsilon, diacylglycerol, type 2 diabetes
- MeSH terms
- Acyl Coenzyme A, Animals, Calorimetry, Carbon Isotopes, Diglycerides, Energy Metabolism, Fatty Liver, Gene Expression Regulation, Glucose, Homeostasis, Insulin, Insulin Resistance, Liver, Mitochondria, Oxidation-Reduction, Triglycerides, Signal Transduction, Muscle, Skeletal, Acyl-CoA Dehydrogenase, Long-Chain, Mice, Protein Kinase C-epsilon
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