Peroxisomal L-bifunctional enzyme (Ehhadh) is essential for the production of medium-chain dicarboxylic acids
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 d...
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doaj-b68d487ec0bf4cc59b2c3909a54bbd9f2021-04-28T05:58:02ZengElsevierJournal of Lipid Research0022-22752012-07-0153712961303Peroxisomal L-bifunctional enzyme (Ehhadh) is essential for the production of medium-chain dicarboxylic acidsSander M. Houten0Simone Denis1Carmen A. Argmann2Yuzhi Jia3Sacha Ferdinandusse4Janardan K. Reddy5Ronald J.A. Wanders6To whom correspondence should be addressed.; Department of Clinical Chemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Laboratory Genetic Metabolic Diseases, and Department of Pediatrics, Academic Medical Center, University of Amsterdam, Amsterdam, The NetherlandsDepartment of Clinical Chemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The NetherlandsEmma Children's Hospital and Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The NetherlandsDepartment of Pathology, Northwestern University Feinberg School of Medicine, Chicago, ILDepartment of Clinical Chemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The NetherlandsDepartment of Pathology, Northwestern University Feinberg School of Medicine, Chicago, ILDepartment of Clinical Chemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Laboratory Genetic Metabolic Diseases, and Department of Pediatrics, Academic Medical Center, University of Amsterdam, Amsterdam, The NetherlandsL-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.http://www.sciencedirect.com/science/article/pii/S0022227520345065peroxisomefatty acid oxidationmouse modelsomega oxidation |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Sander M. Houten Simone Denis Carmen A. Argmann Yuzhi Jia Sacha Ferdinandusse Janardan K. Reddy Ronald J.A. Wanders |
spellingShingle |
Sander M. Houten Simone Denis Carmen A. Argmann Yuzhi Jia Sacha Ferdinandusse Janardan K. Reddy Ronald J.A. Wanders Peroxisomal L-bifunctional enzyme (Ehhadh) is essential for the production of medium-chain dicarboxylic acids Journal of Lipid Research peroxisome fatty acid oxidation mouse models omega oxidation |
author_facet |
Sander M. Houten Simone Denis Carmen A. Argmann Yuzhi Jia Sacha Ferdinandusse Janardan K. Reddy Ronald J.A. Wanders |
author_sort |
Sander M. Houten |
title |
Peroxisomal L-bifunctional enzyme (Ehhadh) is essential for the production of medium-chain dicarboxylic acids |
title_short |
Peroxisomal L-bifunctional enzyme (Ehhadh) is essential for the production of medium-chain dicarboxylic acids |
title_full |
Peroxisomal L-bifunctional enzyme (Ehhadh) is essential for the production of medium-chain dicarboxylic acids |
title_fullStr |
Peroxisomal L-bifunctional enzyme (Ehhadh) is essential for the production of medium-chain dicarboxylic acids |
title_full_unstemmed |
Peroxisomal L-bifunctional enzyme (Ehhadh) is essential for the production of medium-chain dicarboxylic acids |
title_sort |
peroxisomal l-bifunctional enzyme (ehhadh) is essential for the production of medium-chain dicarboxylic acids |
publisher |
Elsevier |
series |
Journal of Lipid Research |
issn |
0022-2275 |
publishDate |
2012-07-01 |
description |
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. |
topic |
peroxisome fatty acid oxidation mouse models omega oxidation |
url |
http://www.sciencedirect.com/science/article/pii/S0022227520345065 |
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