title: Long-chain fatty acid oxidation during early human development.
abstract: Patients with very long-chain acyl-CoA dehydrogenase (VLCAD) and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD)/mitochondrial trifunctional protein (MTP) deficiency, disorders of the mitochondrial long-chain fatty acid oxidation, can present with hypoketotic hypoglycemia, rhabdomyolysis, and cardiomyopathy. In addition, patients with LCHAD/MTP deficiency may suffer from retinopathy and peripheral neuropathy. Until recently, there was no indication of intrauterine morbidity in these disorders. This observation was in line with the widely accepted view that fatty acid oxidation (FAO) does not play a significant role during fetal life. However, the high incidence of the gestational complications acute fatty liver of pregnancy and hemolysis, elevated liver enzymes, and low platelets syndrome observed in mothers carrying a LCHAD/MTP-deficient child and the recent reports of fetal hydrops due to cardiomyopathy in MTP deficiency, as well as the high incidence of intrauterine growth retardation in children with LCHAD/MTP deficiency, suggest that FAO may play an important role during fetal development. In this study, using in situ hybridization of the VLCAD and the LCHAD mRNA, we report on the expression of genes involved in the mitochondrial oxidation of long-chain fatty acids during early human development. Furthermore, we measured the enzymatic activity of the VLCAD, LCHAD, and carnitine palmitoyl-CoA transferase 2 (CPT2) enzymes in different human fetal tissues. Human embryos (at d 35 and 49 of development) and separate tissues (5-20 wk of development) were used. The results show a strong expression of VLCAD and LCHAD mRNA and a high enzymatic activity of VLCAD, LCHAD, and CPT2 in a number of tissues, such as liver and heart. In addition, high expression of LCHAD mRNA was observed in the neural retina and CNS. The observed pattern of expression during early human development is well in line with the spectrum of clinical signs and symptoms reported in patients with VLCAD or LCHAD/MTP deficiency.
authors.affiliation: Department of Pediatrics, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Nadia A
authors.initials: NA
authors.lastname: Oey
authors.forename: Margarethe E J
authors.initials: ME
authors.lastname: den Boer
authors.forename: Frits A
authors.initials: FA
authors.lastname: Wijburg
authors.forename: Michel
authors.initials: M
authors.lastname: Vekemans
authors.forename: Joëlle
authors.initials: J
authors.lastname: Augé
authors.forename: Céline
authors.initials: C
authors.lastname: Steiner
authors.forename: Ronald J A
authors.initials: RJ
authors.lastname: Wanders
authors.forename: Hans R
authors.initials: HR
authors.lastname: Waterham
authors.forename: Jos P N
authors.initials: JP
authors.lastname: Ruiter
authors.forename: Tania
authors.initials: T
authors.lastname: Attié-Bitach
mesh_terms: D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D044942:Acyl-CoA Dehydrogenase, Long-Chain / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D002334:Carnitine O-Palmitoyltransferase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000235:genetics; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D047109:Fetal Development / Q000235:genetics / Q000502:physiology*; D006801:Humans; D017403:In Situ Hybridization; D008052:Lipid Metabolism, Inborn Errors / Q000235:genetics / Q000378:metabolism; D063989:Long-Chain-3-Hydroxyacyl-CoA Dehydrogenase; D008431:Maternal-Fetal Exchange; D063991:Mitochondrial Trifunctional Protein; D009097:Multienzyme Complexes / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D005227:Fatty Acids; D009097:Multienzyme Complexes; D012333:RNA, Messenger; D004247:DNA; D015094:3-Hydroxyacyl CoA Dehydrogenases; D063989:Long-Chain-3-Hydroxyacyl-CoA Dehydrogenase; D044942:Acyl-CoA Dehydrogenase, Long-Chain; D063991:Mitochondrial Trifunctional Protein; D002334:Carnitine O-Palmitoyltransferase