title: Gestational, pathologic and biochemical differences between very long-chain acyl-CoA dehydrogenase deficiency and long-chain acyl-CoA dehydrogenase deficiency in the mouse.
abstract: 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.
authors.affiliation: Department of Genomics and Pathobiology, 1670 University Boulevard, University of Alabama at Birmingham, Birmingham, AL 35294-0019, USA.
authors.forename: K B
authors.initials: KB
authors.lastname: Cox
authors.forename: D A
authors.initials: DA
authors.lastname: Hamm
authors.forename: D S
authors.initials: DS
authors.lastname: Millington
authors.forename: D
authors.initials: D
authors.lastname: Matern
authors.forename: J
authors.initials: J
authors.lastname: Vockley
authors.forename: P
authors.initials: P
authors.lastname: Rinaldo
authors.forename: C A
authors.initials: CA
authors.lastname: Pinkert
authors.forename: W J
authors.initials: WJ
authors.lastname: Rhead
authors.forename: J R
authors.initials: JR
authors.lastname: Lindsey
authors.forename: P A
authors.initials: PA
authors.lastname: Wood
mesh_terms: 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
chemical_list: D005227:Fatty Acids; C116917:acylcarnitine; D044942:Acyl-CoA Dehydrogenase, Long-Chain; D002331:Carnitine