Gestational, pathologic and biochemical differences between very long-chain acyl-CoA dehydrogenase deficiency and long-chain acyl-CoA dehydrogenase deficiency in the mouse.
Although many patients have been found to have very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, none have been documented with long-chain acyl-CoA dehydrogenase (LCAD) deficiency. In order to understand the metabolic pathogenesis of long-chain fatty acid oxidation disorders, we generated mice with VLCAD deficiency (VLCAD(-/-)) and compared their pathologic and biochemical phenotypes of mice with LCAD deficiency (LCAD(-/-)) and wild-type mice. VLCAD(-/-) mice had milder fatty change in liver and heart. Dehydrogenation of various acyl-CoA substrates by liver, heart and skeletal muscle mitochondria differed among the three genotypes. The results for liver were most informative as VLCAD(-/-) mice had a reduction in activity toward palmitoyl-CoA and oleoyl-CoA (58 and 64% of wild-type, respectively), whereas LCAD(-/-) mice showed a more profoundly reduced activity toward these substrates (35 and 32% of wild-type, respectively), with a significant reduction of activity toward the branched chain substrate 2,6-dimethylheptanoyl-CoA. C(16) and C(18) acylcarnitines were elevated in bile, blood and serum of fasted VLCAD(-/-) mice, whereas abnormally elevated C(12) and C(14) acylcarnitines were prominent in LCAD(-/-) mice. Progeny with the combined LCAD(+/+)//VLCAD(+/-) genotype were over-represented in offspring from sires and dams heterozygous for both LCAD and VLCAD mutations. In contrast, no live mice with a compound LCAD(-/-)//VLCAD(-/-) genotype were detected.
Cox
K B
KB
Department of Genomics and Pathobiology, 1670 University Boulevard, University of Alabama at Birmingham, Birmingham, AL 35294-0019, USA.
Hamm
D A
DA
Millington
D S
DS
Matern
D
D
Vockley
J
J
Rinaldo
P
P
Pinkert
C A
CA
Rhead
W J
WJ
Lindsey
J R
JR
Wood
P A
PA
D044942:Acyl-CoA Dehydrogenase, Long-Chain / Q000172:deficiency* / Q000378:metabolism; D000818:Animals; D002331:Carnitine / Q000031:analogs & derivatives* / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D006801:Humans; D008052:Lipid Metabolism, Inborn Errors / Q000201:enzymology* / Q000473:pathology; D008098:Litter Size; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000201:enzymology; D008930:Mitochondria, Liver / Q000201:enzymology; D008931:Mitochondria, Muscle / Q000201:enzymology
D005227:Fatty Acids; C116917:acylcarnitine; D044942:Acyl-CoA Dehydrogenase, Long-Chain; D002331:Carnitine