Slc25a17 Gene Trapped Mice: PMP34 Plays a Role in the Peroxisomal Degradation of Phytanic and Pristanic Acid

Abstract

Mice lacking PMP34, a peroxisomal membrane transporter encoded by Slc25a17, did not manifest any obvious phenotype on a Swiss Webster genetic background, even with various treatments designed to unmask impaired peroxisomal functioning. Peroxisomal αand β-oxidation rates in PMP34 deficient fibroblasts or liver slices were not or only modestly affected and in bile, no abnormal bile acid intermediates were detected. Peroxisomal content of cofactors like CoA, ATP, NAD + , thiamine-pyrophosphate and pyridoxal-phosphate, based on direct or indirect data, appeared normal as were tissue plasmalogen and very long chain fatty acid levels. However, upon dietary phytol administration, the knockout mice displayed hepatomegaly, liver inflammation, and an induction of peroxisomal enzymes. This phenotype was partially mediated by PPARα. Hepatic triacylglycerols and cholesterylesters were elevated and both phytanic acid and pristanic acid accumulated in the liver lipids, in females to higher extent than in males. In addition, pristanic acid degradation products were detected, as wells as the CoAesters of all these branched fatty acids. Hence, PMP34 is important for the degradation of phytanic/pristanic acid and/or export of their metabolites. Whether this is caused by a shortage of peroxisomal CoA affecting the intraperoxisomal formation of pristanoyl-CoA (and perhaps of phytanoyl-CoA), or the SCPx-catalyzed thiolytic cleavage during pristanic acid β-oxidation, could not be proven in this model, but the phytol-derived acyl-CoA profile is compatible with the latter possibility. On the other hand, the normal functioning of other peroxisomal pathways, and especially bile acid formation, seems to exclude severe transport problems or a shortage of CoA, and other cofactors like FAD, NAD(P) + , TPP. Based on our findings, PMP34 deficiency in humans is unlikely to be a life threatening condition but could cause elevated phytanic/pristanic acid levels in older adults.

Peroxisomal Cofactor Transport

“…The in vivo function of SLC25A17 has been further investigated in genetic mutants of orthologs in the model organisms zebrafish ( Danio rerio ) and mice ( Mus musculus ) [ 66 , 67 ]. The zebrafish genome contains two Slc25a17 proteins, which have been both simultaneously down-regulated by a morpholino-based antisense approach [ 66 ].…”

“…Mice lacking the SLC25A17 carrier by insertional mutagenesis did not show any obvious phenotype [ 67 ]. In particular, the diverse functions of the peroxisomal β-oxidation were not compromised in the SLC25A17-deficient mice.…”

“…Upon phytol feeding, the SLC25A17 knockout mice accumulated phytanic and pristanic acid as well as their CoA-esters in the liver, resulting in an enlarged organ and hepatic inflammation [ 67 ]. These abnormalities of the phytol-fed knockout mice suggested that the phytol degradation process depends on the peroxisomal cofactor supplied by SLC25A17.…”

“…These abnormalities of the phytol-fed knockout mice suggested that the phytol degradation process depends on the peroxisomal cofactor supplied by SLC25A17. Unfortunately, the transport function of mice SLC25A17 has not yet been characterized, and thus we can only hypothesize about its preference for ATP, CoA, or NAD as a substrate [ 67 ]. Assuming that mouse SLC25A17 functions as a peroxisomal CoA carrier, as postulated for the zebrafish ortholog, the specific phenotype of the slc25a17-deficient mice might be caused by a shortage of peroxisomal CoA.…”

“…Assuming that mouse SLC25A17 functions as a peroxisomal CoA carrier, as postulated for the zebrafish ortholog, the specific phenotype of the slc25a17-deficient mice might be caused by a shortage of peroxisomal CoA. Since the peroxisomal activation of pristanic acid as well as the thiolytic cleavage during β-oxidation of the resulting medium-chain fatty acids demand free CoA in the peroxisomal matrix, the levels of both phytol-derived fatty acids and acyl-CoA esters were elevated in the liver of the KO mice after phytol feeding [ 67 ].…”