title: Peroxisomal L-bifunctional enzyme (Ehhadh) is essential for the production of medium-chain dicarboxylic acids.
abstract: L-bifunctional enzyme (Ehhadh) is part of the classical peroxisomal fatty acid β-oxidation pathway. This pathway is highly inducible via peroxisome proliferator-activated receptor α (PPARα) activation. However, no specific substrates or functions for Ehhadh are known, and Ehhadh knockout (KO) mice display no appreciable changes in lipid metabolism. To investigate Ehhadh functions, we used a bioinformatics approach and found that Ehhadh expression covaries with genes involved in the tricarboxylic acid cycle and in mitochondrial and peroxisomal fatty acid oxidation. Based on these findings and the regulation of Ehhadh's expression by PPARα, we hypothesized that the phenotype of Ehhadh KO mice would become apparent after fasting. Ehhadh mice tolerated fasting well but displayed a marked deficiency in the fasting-induced production of the medium-chain dicarboxylic acids adipic and suberic acid and of the carnitine esters thereof. The decreased levels of adipic and suberic acid were not due to a deficient induction of ω-oxidation upon fasting, as Cyp4a10 protein levels increased in wild-type and Ehhadh KO mice.We conclude that Ehhadh is indispensable for the production of medium-chain dicarboxylic acids, providing an explanation for the coordinated induction of mitochondrial and peroxisomal oxidative pathways during fasting.
authors.affiliation: Department of Clinical Chemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. s.m.houten@amc.uva.nl
authors.forename: Sander M
authors.initials: SM
authors.lastname: Houten
authors.forename: Simone
authors.initials: S
authors.lastname: Denis
authors.forename: Carmen A
authors.initials: CA
authors.lastname: Argmann
authors.forename: Yuzhi
authors.initials: Y
authors.lastname: Jia
authors.forename: Sacha
authors.initials: S
authors.lastname: Ferdinandusse
authors.forename: Janardan K
authors.initials: JK
authors.lastname: Reddy
authors.forename: Ronald J A
authors.initials: RJ
authors.lastname: Wanders
mesh_terms: D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019295:Computational Biology; D003998:Dicarboxylic Acids / Q000378:metabolism*; D004746:Enoyl-CoA Hydratase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005215:Fasting; D007535:Isomerases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D009097:Multienzyme Complexes / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D063994:Peroxisomal Bifunctional Enzyme; D020675:Peroxisomes / Q000378:metabolism
chemical_list: D003998:Dicarboxylic Acids; D009097:Multienzyme Complexes; D015094:3-Hydroxyacyl CoA Dehydrogenases; C576254:Ehhadh protein, mouse; D004746:Enoyl-CoA Hydratase; D063994:Peroxisomal Bifunctional Enzyme; D007535:Isomerases