Document Detail

Peroxisomal L-bifunctional enzyme (Ehhadh) is essential for the production of medium-chain dicarboxylic acids.
MedLine Citation:
PMID:  22534643     Owner:  NLM     Status:  MEDLINE    
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.
Sander M Houten; Simone Denis; Carmen A Argmann; Yuzhi Jia; Sacha Ferdinandusse; Janardan K Reddy; Ronald J A Wanders
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-04-25
Journal Detail:
Title:  Journal of lipid research     Volume:  53     ISSN:  0022-2275     ISO Abbreviation:  J. Lipid Res.     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-06-11     Completed Date:  2013-02-26     Revised Date:  2013-07-02    
Medline Journal Info:
Nlm Unique ID:  0376606     Medline TA:  J Lipid Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1296-303     Citation Subset:  IM    
Department of Clinical Chemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
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MeSH Terms
3-Hydroxyacyl CoA Dehydrogenases / deficiency,  genetics,  metabolism*
Computational Biology
Dicarboxylic Acids / metabolism*
Enoyl-CoA Hydratase / deficiency,  genetics,  metabolism*
Isomerases / deficiency,  genetics,  metabolism*
Mice, Knockout
Mitochondria / metabolism
Multienzyme Complexes / deficiency,  genetics,  metabolism
Peroxisomes / metabolism
Grant Support
Reg. No./Substance:
0/Dicarboxylic Acids; 0/Multienzyme Complexes; EC CoA Dehydrogenases; EC Hydratase; EC enzyme; EC 5.-/Isomerases

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