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

Paul P Van Veldhoven,Marc Fransen,An Zwijsen,Marc Espeel,Stephen G Young,Myriam Baes,Elke Van Ael,Evelyn De Schryver

doi:10.3389/fcell.2020.00144

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 α- and 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 CoA-esters 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.

Highlights

Peroxisomes are important for β-oxidation of very long chain fatty acids, prostanoids, bile-acid intermediates and pristanic acid, for α-oxidation of phytanic acid and 2-hydroxy fatty acids and for synthesis of the precursors of ether lipids in mammals
The insertion, which contained an engrailed2 splice acceptor site followed by a sequence coding for a promoter less β-geo cassette, results in a fusion transcript consisting of the sequences from the first exon of Slc25a17 (54 coding bases) followed in frame by βgeo sequences
Because phytol causes hepatic peroxisome proliferation and induces many genes involved in lipid and glucose metabolism in rodents, we examined some lipid-related genes in phytolfed mice

Summary

Introduction

Peroxisomes are important for β-oxidation of very long chain fatty acids, prostanoids, bile-acid intermediates and pristanic acid, for α-oxidation of phytanic acid and 2-hydroxy fatty acids and for synthesis of the precursors of ether lipids in mammals. These processes require a continuous flux of substrates, metabolites and cofactors across the peroxisomal membrane, the properties of which are still a matter of debate. ABCD1, one of these ABC-transporters, previously called ALDP, causes X-linked adrenoleukodystrophy in man (Berger and Gartner, 2006) and plays a role in the peroxisomal uptake of very long chain fatty acids and/or their CoA-esters (van Roermund et al, 2008). ABCD3 was recently implicated in bile acid intermediates and pristanic acid degradation (Ferdinandusse et al, 2015)

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