TY - JOUR
T1 - Peroxisomal L-bifunctional enzyme (Ehhadh) is essential for the production of medium-chain dicarboxylic acids
AU - Houten, Sander M.
AU - Denis, Simone
AU - Argmann, Carmen A.
AU - Jia, Yuzhi
AU - Ferdinandusse, Sacha
AU - Reddy, Janardan K.
AU - Wanders, Ronald J. A.
PY - 2012
Y1 - 2012
N2 - L-bifunctional enzyme (Ehhadh) is part of the classical peroxisomal fatty acid beta-oxidation pathway. This pathway is highly inducible via peroxisome proliferator-activated receptor alpha (PPAR alpha) 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 co-varies 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 PPAR alpha, 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 omega-oxidation upon fasting, as Cyp4a10 protein levels increased in wild-type and Ehhadh KO mice.(Jlr) 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.-Houten, S. M., S. Denis, C. A. Argmann, Y. Jia, S. Ferdinandusse, J. K. Reddy, and R. J. A. Wanders. Peroxisomal L-bifunctional enzyme (Ehhadh) is essential for the production of medium-chain dicarboxylic acids. J. Lipid Res. 2012. 53: 1296-1303
AB - L-bifunctional enzyme (Ehhadh) is part of the classical peroxisomal fatty acid beta-oxidation pathway. This pathway is highly inducible via peroxisome proliferator-activated receptor alpha (PPAR alpha) 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 co-varies 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 PPAR alpha, 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 omega-oxidation upon fasting, as Cyp4a10 protein levels increased in wild-type and Ehhadh KO mice.(Jlr) 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.-Houten, S. M., S. Denis, C. A. Argmann, Y. Jia, S. Ferdinandusse, J. K. Reddy, and R. J. A. Wanders. Peroxisomal L-bifunctional enzyme (Ehhadh) is essential for the production of medium-chain dicarboxylic acids. J. Lipid Res. 2012. 53: 1296-1303
U2 - https://doi.org/10.1194/jlr.M024463
DO - https://doi.org/10.1194/jlr.M024463
M3 - Article
C2 - 22534643
SN - 0022-2275
VL - 53
SP - 1296
EP - 1303
JO - Journal of Lipid Research
JF - Journal of Lipid Research
IS - 7
ER -