ACBD5 deficiency is a novel peroxisome disorder with a largely uncharacterized pathology. ACBD5 was recently identified in a tethering complex mediating membrane contacts between peroxisomes and the endoplasmic reticulum (ER). An ACBD5-deficient mouse was analyzed to correlate ACBD5 tethering functions with the disease phenotype. ACBD5-deficient mice exhibit elevated very long-chain fatty acid levels and a progressive cerebellar pathology. Liver did not exhibit pathologic changes but increased peroxisome abundance and drastically reduced peroxisome-ER contacts. Lipidomics of liver and cerebellum revealed tissue-specific alterations in distinct lipid classes and subspecies. In line with the neurological pathology, unusual ultra-long chain fatty acids (C > 32) were elevated in phosphocholines from cerebelli but not liver indicating an organ-specific imbalance in fatty acid degradation and elongation pathways. By contrast, ether lipid formation was perturbed in liver towards an accumulation of alkyldiacylglycerols. The alterations in several lipid classes suggest that ACBD5, in addition to its acyl-CoA binding function, might maintain peroxisome-ER contacts in order to contribute to the regulation of anabolic and catabolic cellular lipid pathways.

ACBD5缺乏症是一种新型的过氧化物酶体紊乱，其病理特征很多。最近在过氧化物酶体和内质网（ER）之间介导膜接触的束缚复合物中鉴定出ACBD5。分析了ACBD5缺陷型小鼠，使ACBD5系链功能与疾病表型相关。ACBD5缺陷小鼠表现出升高的非常长链脂肪酸水平和进行性小脑病理。肝脏未表现出病理变化，但过氧化物酶体丰度增加，而过氧化物酶体-ER接触显着减少。肝脏和小脑的脂质组学揭示了不同脂质类别和亚种的组织特异性改变。与神经病理学一致，不寻常的超长链脂肪酸（C> 32）小脑的磷酸胆碱水平升高，而肝脏则不升高，表明脂肪酸降解和延长途径的器官特异性失衡。相比之下，醚脂质的形成在肝脏中对烷基二酰基甘油的积累有干扰。几种脂质类别的变化表明，ACBD5除其酰基辅酶A结合功能外，还可能维持过氧化物酶体-ER接触，从而有助于合成代谢和分解代谢细胞脂质途径的调控。