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.
Highlights
L-bifunctional enzyme (Ehhadh) is part of the classical peroxisomal fatty acid -oxidation pathway
We combined prior knowledge with gene coexpression subnetworks and mouse experiments to elucidate the role of Ehhadh in metabolism
Ehhadh belongs to the so-called classical peroxisomal -oxidation pathway, together with Acox1 and Acaa1b
Summary
L-bifunctional enzyme (Ehhadh) is part of the classical peroxisomal fatty acid -oxidation pathway. No specific substrates or functions for Ehhadh are known, and Ehhadh knockout (KO) mice display no appreciable changes in lipid metabolism. Mitochondria oxidize the bulk of long-chain fatty acids present in our diet and fat stores, whereas peroxisomes oxidize specific carboxylic acids such as very long-chain fatty acids, branched-chain fatty acids, bile acids, and fatty dicarboxylic acids (DCAs) [1,2,3] Both organelles harbor multiple sets of different enzymes that function in -oxidation. No specific substrates are known for Acaa1a and Acaa1b, they are active toward the 3-ketoacyl-CoA esters of straight-chain fatty acids [5, 6].
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