During fasting, livers from mice lacking Sirt3 had higher levels of fatty acid oxidation intermediate products and triglycerides, associated with decreased levels of fatty acid oxidation, compared to livers from wildtype mice. (2010) demonstrated that Sirt3 ( 604481) expression is upregulated during fasting in liver and brown adipose tissues. (2007) concluded that primary defects in mitochondrial fatty acid oxidation capacity can lead to diacylglycerol accumulation and hepatic insulin resistance. The increase in diacylglycerol concentration was caused by de novo synthesis of diacylglycerol from medium-chain acyl-CoA after insulin stimulation. These changes were associated with increased protein kinase C-epsilon (PRKCE 176975) activity and an aberrant increase in diacylglycerol content after insulin stimulation.
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The defect in insulin action was associated with reduced Irs2 ( 600797)-associated PI3-kinase (see 601232) activity and reduced Akt2 ( 164731) activation. (2007) found that Lcad-knockout mice developed hepatic steatosis associated with hepatic insulin resistance. These results demonstrated the crucial roles of mitochondrial fatty acid oxidation and LCAD in vivo. Approximately 10% of adult Lcad -/- males developed cardiomyopathy, and sudden death was observed in 4 of 75 Lcad -/- mice.
#Long chain acyl coa dehydrogenase deficiency nbme 16 free
Lcad -/- mice that reached birth appeared normal, but had severely reduced fasting tolerance with hepatic and cardiac lipidosis, hypoglycemia, elevated serum free fatty acids, and nonketotic dicarboxylic aciduria. Matings between heterozygous mice yielded an abnormally low number of Lcad heterozygous and homozygous deficient offspring, indicating frequent gestational loss. (1998) produced a mouse model of LCAD deficiency with severely impaired fatty acid oxidation. Mutations in both the Acadl and Acads genes attenuated the induction of genes normally responsive to adrenergic signaling in brown adipocytes, suggesting that the mutant mice had a perturbation in the action of fatty acids as regulators of gene expression. The cold sensitivity resembled that described for mice with a defect in nonshivering thermogenesis due to the targeted inactivation of the brown adipocyte-specific mitochondrial uncoupling protein gene, Ucp1 ( 113730). (1998) found that mice with targeted inactivation of the long-chain acyl-CoA dehydrogenase gene (Acadl) are sensitive to the cold, similar to BALB/cByJ mice who have mutations in the Acads gene (see 201470).