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

DM Kurtz, P Rinaldo, WJ Rhead… - Proceedings of the …, 1998 - National Acad Sciences
DM Kurtz, P Rinaldo, WJ Rhead, L Tian, DS Millington, J Vockley, DA Hamm, AE Brix…
Proceedings of the National Academy of Sciences, 1998National Acad Sciences
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 …
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.
National Acad Sciences