Targeted Disruption of Mouse Long-Chain Acyl-CoA Dehydrogenase Gene Reveals Crucial Roles for Fatty Acid Oxidation

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 95; no. 26; pp. 15592 - 15597
• Main Authors: Kurtz, David M., Rinaldo, Piero, Rhead, William J., Tian, Liqun, Millington, David S., Vockley, Jerry, Hamm, Doug A., Brix, Amy E., Lindsey, J. Russell, Pinkert, Carl A., O'Brien, William E., Wood, Philip A.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 22.12.1998; National Acad Sciences; National Academy of Sciences; The National Academy of Sciences
• Subjects: Acyl-CoA Dehydrogenase, Long-Chain - deficiency; Acyl-CoA Dehydrogenase, Long-Chain - genetics; Acyl-CoA Dehydrogenase, Long-Chain - metabolism; Animals; Biological Sciences; Dehydrogenases; Disease Models, Animal; Enzymes; Exons; Fasting; Fatty acids; Fatty Acids, Nonesterified - blood; Fatty Acids, Nonesterified - metabolism; Genes; Humans; Lipid Metabolism, Inborn Errors - enzymology; Lipid Metabolism, Inborn Errors - genetics; Lipid Metabolism, Inborn Errors - pathology; Liver - metabolism; Liver - pathology; Metabolic diseases; Mice; Mice, Knockout; Mitochondria, Liver - enzymology; Muscle, Skeletal - metabolism; Nonesterified fatty acids; Oxidation; Pups; Rodents; Substrate Specificity
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.95.26.15592

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.