TY - JOUR
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
N1 - Funding Information:
Supported in part by a grant from National Institutes of Health (DK-56345) and a Venture Fund from Wake Forest University School of Medicine (to J.A.I.).
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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U2 - 10.1053/j.gastro.2005.02.001
DO - 10.1053/j.gastro.2005.02.001
M3 - Article
C2 - 15887119
AN - SCOPUS:21044438592
SN - 0016-5085
VL - 128
SP - 1381
EP - 1390
JO - Gastroenterology
JF - Gastroenterology
IS - 5
ER -