Van Veldhoven Paul P, de Schryver Evelyn, Young Stephen G, Zwijsen An, Fransen Marc, Espeel Marc, Baes Myriam, Van Ael Elke
LIPIT, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
Departments of Medicine and Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.
Front Cell Dev Biol. 2020 Mar 24;8:144. doi: 10.3389/fcell.2020.00144. eCollection 2020.
Mice lacking PMP34, a peroxisomal membrane transporter encoded by , 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.
缺乏由[具体基因]编码的过氧化物酶体膜转运蛋白PMP34的小鼠，在瑞士韦伯斯特遗传背景下未表现出任何明显的表型，即使采用了各种旨在揭示过氧化物酶体功能受损的处理方法。PMP34缺陷型成纤维细胞或肝切片中的过氧化物酶体α-氧化和β-氧化速率未受影响或仅受到轻微影响，并且在胆汁中未检测到异常的胆汁酸中间体。基于直接或间接数据，辅酶如辅酶A、ATP、NAD、硫胺焦磷酸和磷酸吡哆醛的过氧化物酶体含量似乎正常，组织缩醛磷脂和极长链脂肪酸水平也是如此。然而，在给予膳食植醇后，基因敲除小鼠出现肝肿大、肝脏炎症以及过氧化物酶体酶的诱导。这种表型部分由PPARα介导。肝脏三酰甘油和胆固醇酯升高，植烷酸和降植烷酸都在肝脏脂质中积累，雌性比雄性积累程度更高。此外，检测到了降植烷酸降解产物以及所有这些支链脂肪酸的辅酶A酯。因此，PMP34对于植烷酸/降植烷酸的降解和/或其代谢产物的输出很重要。这是由于过氧化物酶体辅酶A短缺影响了过氧化物酶体内降植烷酰辅酶A（可能还有植烷酰辅酶A）的形成，还是由于降植烷酸β-氧化过程中SCPx催化的硫解裂解，在该模型中无法得到证实，但植醇衍生的酰基辅酶A谱与后一种可能性相符。另一方面，其他过氧化物酶体途径的正常功能，尤其是胆汁酸形成，似乎排除了严重的转运问题或辅酶A以及其他辅因子如FAD、NAD(P)、TPP的短缺。基于我们的研究结果，人类PMP34缺乏不太可能是危及生命的状况，但可能导致老年人植烷酸/降植烷酸水平升高。
