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Targeted disruption of mouse long-chain acyl-CoA dehydrogenase gene reveals crucial roles for fatty acid oxidation.

Abnormalities of fatty acid metabolism are recognized to play a significant role in human disease, but the mechanisms remain poorly understood. Long-chain acyl-CoA dehydrogenase (LCAD) catalyzes the initial step in mitochondrial fatty acid oxidation (FAO). We produced a mouse model of LCAD deficiency with severely impaired FAO. Matings between LCAD +/- mice yielded an abnormally low number of LCAD +/- and -/- offspring, indicating frequent gestational loss. 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. Approximately 10% of adult LCAD -/- males developed cardiomyopathy, and sudden death was observed in 4 of 75 LCAD -/- mice. These results demonstrate the crucial roles of mitochondrial FAO and LCAD in vivo.

Pubmed ID: 9861014

Authors

  • Kurtz DM
  • Rinaldo P
  • Rhead WJ
  • Tian L
  • Millington DS
  • Vockley J
  • Hamm DA
  • Brix AE
  • Lindsey JR
  • Pinkert CA
  • O'Brien WE
  • Wood PA

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Data

December 22, 1998

Associated Grants

  • Agency: NCI NIH HHS, Id: P30CA-13148
  • Agency: NIDDK NIH HHS, Id: R01-DK45482
  • Agency: NCRR NIH HHS, Id: R01-RR02599

Mesh Terms

  • Acyl-CoA Dehydrogenase, Long-Chain
  • Animals
  • Disease Models, Animal
  • Fatty Acids, Nonesterified
  • Humans
  • Lipid Metabolism, Inborn Errors
  • Liver
  • Mice
  • Mice, Knockout
  • Mitochondria, Liver
  • Muscle, Skeletal
  • Substrate Specificity