title: Mitochondrial long chain fatty acid beta-oxidation in man and mouse.
abstract: Several mouse models for mitochondrial fatty acid beta-oxidation (FAO) defects have been developed. So far, these models have contributed little to our current understanding of the pathophysiology. The objective of this study was to explore differences between murine and human FAO. Using a combination of analytical, biochemical and molecular methods, we compared fibroblasts of long chain acyl-CoA dehydrogenase knockout (LCAD(-/-)), very long chain acyl-CoA dehydrogenase knockout (VLCAD(-/-)) and wild type mice with fibroblasts of VLCAD-deficient patients and human controls. We show that in mice, LCAD and VLCAD have overlapping and distinct roles in FAO. The absence of VLCAD is apparently fully compensated, whereas LCAD deficiency is not. LCAD plays an essential role in the oxidation of unsaturated fatty acids such as oleic acid, but seems redundant in the oxidation of saturated fatty acids. In strong contrast, LCAD is neither detectable at the mRNA level nor at the protein level in men, making VLCAD indispensable in FAO. Our findings open new avenues to employ the existing mouse models to study the pathophysiology of human FAO defects.
authors.affiliation: Department of Clinical Chemistry, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, The Netherlands.
authors.forename: Malika
authors.initials: M
authors.lastname: Chegary
authors.forename: Heleen te
authors.initials: Ht
authors.lastname: Brinke
authors.forename: Jos P N
authors.initials: JP
authors.lastname: Ruiter
authors.forename: Frits A
authors.initials: FA
authors.lastname: Wijburg
authors.forename: Maria S K
authors.initials: MS
authors.lastname: Stoll
authors.forename: Paul E
authors.initials: PE
authors.lastname: Minkler
authors.forename: Michel
authors.initials: M
authors.lastname: van Weeghel
authors.forename: Horst
authors.initials: H
authors.lastname: Schulz
authors.forename: Charles L
authors.initials: CL
authors.lastname: Hoppel
authors.forename: Ronald J A
authors.initials: RJ
authors.lastname: Wanders
authors.forename: Sander M
authors.initials: SM
authors.lastname: Houten
mesh_terms: D044942:Acyl-CoA Dehydrogenase, Long-Chain / Q000172:deficiency; D000818:Animals; D002331:Carnitine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D005227:Fatty Acids / Q000378:metabolism*; D005347:Fibroblasts / Q000201:enzymology; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D010084:Oxidation-Reduction; D053719:Tandem Mass Spectrometry
chemical_list: D005227:Fatty Acids; C116917:acylcarnitine; D044942:Acyl-CoA Dehydrogenase, Long-Chain; D002331:Carnitine