Mice heterozygous for a defect in mitochondrial trifunctional protein develop hepatic steatosis and insulin resistance.
OBJECTIVE
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.
Ibdah
Jamal A
JA
Division of Gastroenterology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA. jibdah@wfubmc.edu
Perlegas
Peter
P
Zhao
Yiwen
Y
Angdisen
Jerry
J
Borgerink
Hermina
H
Shadoan
Melanie K
MK
Wagner
Janice D
JD
Matern
Dietrich
D
Rinaldo
Piero
P
Cline
J Mark
JM
D000818:Animals; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D006579:Heterozygote; D007333:Insulin Resistance / Q000235:genetics*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D063991:Mitochondrial Trifunctional Protein; D009097:Multienzyme Complexes / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology
D005227:Fatty Acids; D009097:Multienzyme Complexes; D063991:Mitochondrial Trifunctional Protein