Mice heterozygous for a defect in mitochondrial trifunctional protein develop hepatic steatosis and insulin resistance

Jamal A. Ibdah, Peter Perlegas, Yiwen Zhao, Jerry Angdisen, Hermina Borgerink, Melanie K. Shadoan, Janice D. Wagner, Dietrich Matern, Piero Rinaldo, J. Mark Cline

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Abstract

Background & Aims: Little is known about the role of mitochondrial β-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 β-oxidation defects predisposes to NAFLD and insulin resistance in aging mice. Impairment of mitochondrial β-oxidation may play an important role in pathogenesis of NAFLD.

Original languageEnglish (US)
Pages (from-to)1381-1390
Number of pages10
JournalGastroenterology
Volume128
Issue number5
DOIs
StatePublished - May 2005

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Mitochondrial Trifunctional Protein
Insulin Resistance
Liver
Insulin
Fatty Acids
Glucose Tolerance Test
Glutathione Peroxidase
Alanine Transaminase
Glucose
Cytochrome P-450 Enzyme System
Superoxide Dismutase
Area Under Curve
Oxidative Stress
Disease Resistance
Hyperinsulinism
Glutathione
Triglycerides
Antioxidants

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Ibdah, J. A., Perlegas, P., Zhao, Y., Angdisen, J., Borgerink, H., Shadoan, M. K., ... Cline, J. M. (2005). Mice heterozygous for a defect in mitochondrial trifunctional protein develop hepatic steatosis and insulin resistance. Gastroenterology, 128(5), 1381-1390. https://doi.org/10.1053/j.gastro.2005.02.001

Mice heterozygous for a defect in mitochondrial trifunctional protein develop hepatic steatosis and insulin resistance. / Ibdah, Jamal A.; Perlegas, Peter; Zhao, Yiwen; Angdisen, Jerry; Borgerink, Hermina; Shadoan, Melanie K.; Wagner, Janice D.; Matern, Dietrich; Rinaldo, Piero; Cline, J. Mark.

In: Gastroenterology, Vol. 128, No. 5, 05.2005, p. 1381-1390.

Research output: Contribution to journalArticle

Ibdah, JA, Perlegas, P, Zhao, Y, Angdisen, J, Borgerink, H, Shadoan, MK, Wagner, JD, Matern, D, Rinaldo, P & Cline, JM 2005, 'Mice heterozygous for a defect in mitochondrial trifunctional protein develop hepatic steatosis and insulin resistance', Gastroenterology, vol. 128, no. 5, pp. 1381-1390. https://doi.org/10.1053/j.gastro.2005.02.001
Ibdah, Jamal A. ; Perlegas, Peter ; Zhao, Yiwen ; Angdisen, Jerry ; Borgerink, Hermina ; Shadoan, Melanie K. ; Wagner, Janice D. ; Matern, Dietrich ; Rinaldo, Piero ; Cline, J. Mark. / Mice heterozygous for a defect in mitochondrial trifunctional protein develop hepatic steatosis and insulin resistance. In: Gastroenterology. 2005 ; Vol. 128, No. 5. pp. 1381-1390.
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abstract = "Background & Aims: Little is known about the role of mitochondrial β-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 β-oxidation defects predisposes to NAFLD and insulin resistance in aging mice. Impairment of mitochondrial β-oxidation may play an important role in pathogenesis of NAFLD.",
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T1 - Mice heterozygous for a defect in mitochondrial trifunctional protein develop hepatic steatosis and insulin resistance

AU - Ibdah, Jamal A.

AU - Perlegas, Peter

AU - Zhao, Yiwen

AU - Angdisen, Jerry

AU - Borgerink, Hermina

AU - Shadoan, Melanie K.

AU - Wagner, Janice D.

AU - Matern, Dietrich

AU - Rinaldo, Piero

AU - Cline, J. Mark

PY - 2005/5

Y1 - 2005/5

N2 - Background & Aims: Little is known about the role of mitochondrial β-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 β-oxidation defects predisposes to NAFLD and insulin resistance in aging mice. Impairment of mitochondrial β-oxidation may play an important role in pathogenesis of NAFLD.

AB - Background & Aims: Little is known about the role of mitochondrial β-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 β-oxidation defects predisposes to NAFLD and insulin resistance in aging mice. Impairment of mitochondrial β-oxidation may play an important role in pathogenesis of NAFLD.

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