Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
iPSC/CRISPR Center Groningen, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Sci Rep. 2022 Feb 15;12(1):2512. doi: 10.1038/s41598-022-06479-y.
Peroxisomes play an important role in the metabolism of a variety of biomolecules, including lipids and bile acids. Peroxisomal Membrane Protein 4 (PXMP4) is a ubiquitously expressed peroxisomal membrane protein that is transcriptionally regulated by peroxisome proliferator-activated receptor α (PPARα), but its function is still unknown. To investigate the physiological function of PXMP4, we generated a Pxmp4 knockout (Pxmp4) mouse model using CRISPR/Cas9-mediated gene editing. Peroxisome function was studied under standard chow-fed conditions and after stimulation of peroxisomal activity using the PPARα ligand fenofibrate or by using phytol, a metabolite of chlorophyll that undergoes peroxisomal oxidation. Pxmp4 mice were viable, fertile, and displayed no changes in peroxisome numbers or morphology under standard conditions. Also, no differences were observed in the plasma levels of products from major peroxisomal pathways, including very long-chain fatty acids (VLCFAs), bile acids (BAs), and BA intermediates di- and trihydroxycholestanoic acid. Although elevated levels of the phytol metabolites phytanic and pristanic acid in Pxmp4 mice pointed towards an impairment in peroxisomal α-oxidation capacity, treatment of Pxmp4 mice with a phytol-enriched diet did not further increase phytanic/pristanic acid levels. Finally, lipidomic analysis revealed that loss of Pxmp4 decreased hepatic levels of the alkyldiacylglycerol class of neutral ether lipids, particularly those containing polyunsaturated fatty acids. Together, our data show that while PXMP4 is not critical for overall peroxisome function under the conditions tested, it may have a role in the metabolism of (ether)lipids.
过氧化物酶体在多种生物分子的代谢中发挥着重要作用，包括脂质和胆汁酸。过氧化物酶体膜蛋白 4（PXMP4）是一种广泛表达的过氧化物酶体膜蛋白，其转录受过氧化物酶体增殖物激活受体 α（PPARα）调控，但功能尚不清楚。为了研究 PXMP4 的生理功能，我们使用 CRISPR/Cas9 介导的基因编辑生成了 Pxmp4 敲除（Pxmp4）小鼠模型。在标准饲料喂养条件下以及在用 PPARα 配体非诺贝特或叶绿素代谢物植醇刺激过氧化物酶体活性后，研究了过氧化物酶体的功能，植醇在过氧化物酶体中发生氧化。Pxmp4 小鼠具有活力，可育，在标准条件下过氧化物酶体数量或形态没有变化。此外，在主要过氧化物酶体途径的产物（包括超长链脂肪酸（VLCFAs）、胆汁酸（BAs）和 BAs 中间体二羟胆烷酸和三羟胆烷酸）的血浆水平上也没有观察到差异。尽管 Pxmp4 小鼠中植醇代谢物植烷酸和姥鲛烷酸水平升高表明过氧化物酶体 α-氧化能力受损，但用富含植醇的饮食治疗 Pxmp4 小鼠并没有进一步增加植烷酸/姥鲛烷酸水平。最后，脂质组学分析表明，Pxmp4 的缺失降低了肝脏中性醚脂类中烷二酰甘油类的水平，特别是那些含有多不饱和脂肪酸的醚脂。总之，我们的数据表明，尽管在测试条件下 PXMP4 对于过氧化物酶体的整体功能不是必需的，但它可能在（醚）脂类的代谢中发挥作用。
