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. C16 and C18 acylcarnitines were elevated in bile, blood and serum of fasted VLCAD-/- mice, whereas abnormally elevated C12 and C14 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.
ASJC Scopus subject areas
- Molecular Biology