Mice Heterozygous for a Defect in Mitochondrial Trifunctional Protein Develop Hepatic Steatosis and Insulin Resistance
Open accessAbstract
Background & aims Little is known about the role of mitochondrial beta-oxidation in development of nonalcoholic fatty liver disease (NAFLD). Mitochondrial trifunctional protein (MTP) catalyzes long-chain fatty acid oxidation. Recently, we generated a mouse model for MTP deficiency and reported that homozygous (MTPa-/-) mice suffer neonatal death. In this study, we investigated effects of heterozygosity for the MTP defect on hepatic oxidative stress, insulin resistance, and development of NAFLD in mice. Methods We evaluated liver histopathology, serum alanine aminotransferase (ALT), glucose, fatty acids, and insulin levels in MTPa+/- and MTPa+/+ littermates. Insulin resistance was evaluated using glucose tolerance test (GTT) and insulin tolerance test (ITT). Liver tissues were used to measure triglyceride and fatty acid content, activity of superoxide dismutases (SOD) and glutathione peroxidase (GPx), glutathione (GSH), and cytochrome P-450 2E1 expression. Results Aging but not young MTPa+/- mice developed hepatic steatosis with elevated ALT, basal hyperinsulinemia, and increased insulin area under curve (AUC) on GTT compared with MTPa+/+ littermates. In response to insulin challenge, aging MTPa+/- mice had slower rate of glucose disappearance and increased glucose AUC. Significant hepatic steatosis and insulin resistance developed concomitantly in the MTPa+/- mice at 9-10 months of age. Aging MTPa+/- mice had higher antioxidant activity of total SOD and GPx, lower GSH, and increased expression of cytochrome P-450 2E1, consistent with increased hepatic oxidative stress. Conclusions Heterozygosity for beta-oxidation defects predisposes to NAFLD and insulin resistance in aging mice. Impairment of mitochondrial beta-oxidation may play an important role in pathogenesis of NAFLD.
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Reduction of one subunit of the mitochondrial trifunctional protein in heterozygote knock-out mice leads to concomitant reduction of the other subunit.
“Previous studies have shown that reduction of one or the other component in heterozygote knock-out mice leads to a concomitant reduction of the other subunit (31)(32)(33).”
From Expression of miR-33 from an SREBP2 Intron Inhibits Cholesterol Export and Fatty Acid Oxidation* (2010) · cites this paper as [32]
The Assessment of the Temporal Relationship section (page unavailable) reports lower hepatic MTP α-subunit expression in α-heterozygous mice than in wild-type mice. The Background & Aims section says α-null homozygotes lack both subunits, but the paper does not show a concomitant reduction of the β-subunit in heterozygotes or examine β-heterozygous knockouts. (LLM, conf=0.85)
Experimental — accuracy not yet measuredHepatic steatosis was observed both in mice carrying a hypomorphic allele of HADHB and in mice heterozygous for a null mutation of HADHA.
“This was observed both in mice that carry a hypomorphic allele of the HADHB gene and, notably, in mice heterozygote for a null mutation of the HADHA gene (encoding the ␣-subunit) (32,33).”
From Expression of miR-33 from an SREBP2 Intron Inhibits Cholesterol Export and Fatty Acid Oxidation* (2010) · cites this paper as [32]
Reduced gene dosage or activity of the mitochondrial trifunctional protein complex leads to the accumulation of lipids in the liver (hepatic steatosis).
“Surprisingly, there is evidence that reduced gene dosage or activity of this enzyme complex leads to the accumulation of lipids in the liver (hepatic steatosis) (32,33).”
From Expression of miR-33 from an SREBP2 Intron Inhibits Cholesterol Export and Fatty Acid Oxidation* (2010) · cites this paper as [32]
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References 32 · Cited by 186
Research works printed but not linked: 25
- Falck-Ytter Y, Younossi ZM, Marchesini G, McCullough AJ. Clinical features and natural history of nonalcoholic steatosis syn- dromes. Semin Liver Dis 2001;21:17-26.
- Clark JM, Brancati FL, Diehl AM. Nonalcoholic fatty liver disease. Gastroenterology 2002;122:1649 -1657.
- Jackson S, Kler RS, Bartlett K, Briggs H, Bindoff LA, Pourfarzam M, Gardner-Medwin D, Turnbull DM. Combined enzyme defect of mito- chondrial fatty acid oxidation. J Clin Invest 1992;90:1219 -1225.
- Ushikubo S, Aoyama T, Kamijo T, Wanders RJ, Rinaldo P, Vockley J, Hashimoto T. Molecular characterization of mitochondrial tri- functional protein deficiency: formation of the enzyme complex is important for stabilization of both ␣-and -subunits. Am J Hum Genet 1996;58:979 -988.
- Kamijo T, Wanders RJ, Saudubray JM, Aoyama T, Komiyama A, Hashimoto T. Mitochondrial trifunctional protein deficiency. Cat- alytic heterogeneity of the mutant enzyme in two patients. J Clin Invest 1994;93:1740 -1747.
- Sims HF, Brackett JC, Powell CK, Treem WR, Hale DE, Bennett MJ, Gibson B, Shapiro S, Strauss AW. The molecular basis of pediatric long chain 3-hydroxyacyl-CoA dehydrogenase deficiency associated with maternal acute fatty liver of pregnancy. Proc Natl Acad Sci U S A 1995;92:841-845.
- Aoyama T, Wakui K, Orii KE, Hashimoto T, Fukushima Y. Fluores- cence in situ hybridization mapping of the ␣ and  subunits (HADHA and HADHB) of human mitochondrial fatty acid beta- oxidation multienzyme complex to 2p23 and their evolution. Cy- togenet Cell Genet 1997;79:221-224.
- Brackett JC, Sims HF, Rinaldo P, Shapiro S, Powell CK, Bennett MJ, Strauss AW. Two ␣ subunit donor splice site mutations cause human trifunctional protein deficiency. J Clin Invest 1995;95: 2076 -2082.
- Ijlst L, Ruiter JP, Hoovers JM, Jakobs ME, Wanders RJ. Common missense mutation G1528C in long-chain 3-hydroxyacyl-CoA de- hydrogenase deficiency. Characterization and expression of the mutant protein, mutation analysis on genomic DNA and chromo- somal localization of the mitochondrial trifunctional protein ␣ subunit gene. J Clin Invest 1996;98:1028 -1033.
- Ibdah JA, Tein I, Dionisi-Vici C, Bennett MJ, Ijlst L, Gibson B, Wanders RJ, Strauss AW. Mild trifunctional protein deficiency is associated with progressive neuropathy and myopathy and sug- gests a novel genotype-phenotype correlation. J Clin Invest 1998; 102:1193-1199.
- Ibdah JA, Bennett MJ, Rinaldo P, Zhao Y, Gibson B, Sims HF, Strauss AW. A fetal fatty-acid oxidation disorder as a cause of liver disease in pregnant women. N Engl J Med 1999;340:1723-1731.
- Yang Z, Zhao Y, Bennett MJ, Strauss AW, Ibdah JA. Fetal geno- types and pregnancy outcomes in 35 families with mitochondrial trifunctional protein mutations. Am J Obstet Gynecol 2002;187: 715-720.
- Yang Z, Yamada J, Zhao Y, Strauss AW, Ibdah JA. Prospective screening for pediatric mitochondrial trifunctional protein defects in pregnancies complicated by liver disease. JAMA 2002;288: 2163-2166.
- Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander-Tetri BA, Bacon BR. Non-alcoholic steatohepatitis: a proposal of grading and staging the histological lesions. Am J Gastroenterol 1999; 94:2467-2474.
- Carr TP, Andresen CJ, Rudel LL. Enzymatic determination of triglyceride, free cholesterol, and total cholesterol in tissue lipid extracts. Clin Biochem 1993;26:39 -42.
- Boles RG, Martin SK, Blitzer MG, Rinaldo P. Biochemical diagno- sis of fatty acid oxidation disorders by metabolite analysis of postmortem liver. Hum Pathol 1994; 25:735-741.
- Bonora E, Moghetti P, Zancanaro C, Cigolini M, Querena M, Cacciatori V, Corgnati A, Muggeo M. Estimates of in vivo insulin action in man: comparison of insulin tolerance tests with eugly- cemic and hyperglycemic glucose clamp studies. J Clin Endocri- nol Metab 1989;68:374 -378.
- Weltman MD, Farrell GC, Hall P, Ingelman-Sundberg M, Liddle C. Hepatic cytochrome P450 2E1 is increased in patients with nonalcoholic steatohepatitis. Hepatology 1998;27:128 -133.
- Day CP, James OF. Steatohepatitis: a tale of two "hits"? Gastro- enterology 1998;114:842-845.
- Zytkovicz TH, Fitzgerald EF, Marsden D, Larson CA, Shih VE, Johnson DM, Strauss AW, Comeau AM, Eaton RB, Grady GF. Tandem mass spectrometric analysis for amino, organic, and fatty acid disorders in newborn dried blood spots: a two-year summary from the New England Newborn Screening Program. Clin Chem 2001;47:1945-1955.
- Oakes ND, Cooney GJ, Camilleri S, Chisholm DJ, Kraegen EW. Mechanisms of liver and muscle insulin resistance induced by chronic high-fat feeding. Diabetes 1997;46:1768 -1774.
- Petersen KF, Befroy D, Dufour S, Dziura J, Ariyan C, Rothman DL, DiPietro L, Cline GW, Shulman GI. Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science 2003; 300:1140 -1142.
- Roden M, Price TB, Perseghin G, Petersen KF, Rothman DL, Cline GW, Shulman GI. Mechanism of free fatty acid-induced insulin resistance in humans. J Clin Invest 1996;97:2859 -2865.
- Dresner A, Laurent D, Marcucci M, Griffin ME, Dufour S, Cline GW, Slezak LA, Andersen DK, Hundal RS, Rothman DL, Petersen KF, Shulman GI. Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. J Clin Invest 1999;103:253-259.
- Wiesenthal SR, Sandhu H, McCall RH, Tchipashvili V, Yoshii H, Polonsky K, Shi ZQ, Lewis GF, Mari A, Giacca A. Free fatty acids impair hepatic insulin extraction in vivo. Diabetes 1999;48:766 - 774.
- Authors
- Ibdah, J. A., Perlegas, P., Zhao, Y., Angdisen, J., Borgerink, H., Shadoan, M. K., Wagner, J. D., Matern, D., Rinaldo, P., & Cline, J. M.
- Affiliations
- Wake Forest University Health Sciences (US)
- Mayo Clinic (US)
- Corresponding author
- Ibdah, Jamal A.
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2005-05
- Volume
- 128
- Issue
- 5
- Pages
- 1381-1390
- ISSN
- 0016-5085 (ISSN-L)
- OpenAlex
- W2131375116
- Cited by
- 186
- References
- 32
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 6 · 2023: 11 · 2022: 7 · 2021: 4 · 2020: 15 · 2019: 8 · 2018: 8 · 2017: 16 · 2016: 8 · 2015: 16 · 2014: 10 · 2013: 8 · 2012: 9
- FWCI
- 5.28
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wake Forest University
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-56345, R01DK056345)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- mitochondrial trifunctional protein, non-alcoholic fatty liver disease, hepatic steatosis, insulin resistance, mitochondrial beta-oxidation, long-chain fatty acid oxidation, hepatic oxidative stress, aging, hyperinsulinemia, glucose tolerance, antioxidant enzymes, glutathione, CYP2E1
- MeSH terms
- Animals, Fatty Acids, Fatty Liver, Heterozygote, Insulin Resistance, Liver, Multienzyme Complexes, Mice, Knockout, Oxidative Stress, Mice, Mitochondrial Trifunctional Protein
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