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.
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.
Authors: Matthew J Laye; R Scott Rector; Sarah J Borengasser; Scott P Naples; Grace M Uptergrove; Jamal A Ibdah; Frank W Booth; John P Thyfault Journal: J Appl Physiol (1985) Date: 2008-10-30
Authors: R Scott Rector; John P Thyfault; Grace M Uptergrove; E Matthew Morris; Scott P Naples; Sarah J Borengasser; Catherine R Mikus; Matthew J Laye; M Harold Laughlin; Frank W Booth; Jamal A Ibdah Journal: J Hepatol Date: 2010-03-04 Impact factor: 25.083
Authors: John P Thyfault; R Scott Rector; Grace M Uptergrove; Sarah J Borengasser; E Matthew Morris; Yongzhong Wei; Matt J Laye; Charles F Burant; Nathan R Qi; Suzanne E Ridenhour; Lauren G Koch; Steve L Britton; Jamal A Ibdah Journal: J Physiol Date: 2009-02-23 Impact factor: 5.182
Authors: Sathish Kumar Natarajan; Kavitha R Thangaraj; Ashish Goel; C E Eapen; K A Balasubramanian; Anup Ramachandran Journal: Obstet Med Date: 2011-07-04