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.
Kurtz
D M
DM
Department of Comparative Medicine, Schools of Medicine and Dentistry, University of Alabama, Birmingham, AL 35294, USA.
Rinaldo
P
P
Rhead
W J
WJ
Tian
L
L
Millington
D S
DS
Vockley
J
J
Hamm
D A
DA
Brix
A E
AE
Lindsey
J R
JR
Pinkert
C A
CA
O'Brien
W E
WE
Wood
P A
PA
D044942:Acyl-CoA Dehydrogenase, Long-Chain / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D005230:Fatty Acids, Nonesterified / Q000097:blood / Q000378:metabolism; D006801:Humans; D008052:Lipid Metabolism, Inborn Errors / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000201:enzymology; D018482:Muscle, Skeletal / Q000378:metabolism; D013379:Substrate Specificity
D005230:Fatty Acids, Nonesterified; D044942:Acyl-CoA Dehydrogenase, Long-Chain