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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

To unravel the conflicting data concerning the dependence of human cholesterol biosynthesis on functional peroxisomes, we determined activities and levels of selected enzymes involved in cholesterol biosynthesis in livers of PEX5 knockout mice, a well-characterized model for human Zellweger syndrome. We found that all enzymes measured, including putative peroxisomal enzymes, are at least as active in the peroxisome-deficient Zellweger mice as in control mice, indicating that mislocalization of enzymes to the cytosol does not lead to decreased activity or degradation. Prompted by these results, we re-examined this aspect in human subjects by specific enzyme activity measurements and immunoblotting with highly specific antisera. Our results show that the previously reported deficiencies of mevalonate kinase and phosphomevalonate kinase activity in livers from human Zellweger patients reflect the bad condition of the livers, rather than mislocalization to the cytosol. Our data provide an explanation for the conflicting findings in the literature and show that great care should be taken in the interpretation of data obtained in postmortem material. —Hogenboom, S., G. J. Romeijn, S. M. Houten, M. Baes, R. J. A. Wanders, and H. R. Waterham. Absence of functional peroxisomes does not lead to deficiency of enzymes involved in cholesterol biosynthesis. J. Lipid Res. 2002. 43: 90–98.