Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, TX, United States of America.
Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China.
PLoS One. 2021 Apr 1;16(4):e0248964. doi: 10.1371/journal.pone.0248964. eCollection 2021.
Emerging studies indicate that APOA-I binding protein (AIBP) is a secreted protein and functions extracellularly to promote cellular cholesterol efflux, thereby disrupting lipid rafts on the plasma membrane. AIBP is also present in the mitochondria and acts as an epimerase, facilitating the repair of dysfunctional hydrated NAD(P)H, known as NAD(P)H(X). Importantly, AIBP deficiency contributes to lethal neurometabolic disorder, reminiscent of the Leigh syndrome in humans. Whereas cyclic NADPHX production is proposed to be the underlying cause, we hypothesize that an unbiased metabolic profiling may: 1) reveal new clues for the lethality, e.g., changes of mitochondrial metabolites., and 2) identify metabolites associated with new AIBP functions. To this end, we performed unbiased and profound metabolic studies of plasma obtained from adult AIBP knockout mice and control littermates of both genders. Our systemic metabolite profiling, encompassing 9 super pathways, identified a total of 640 compounds. Our studies demonstrate a surprising sexual dimorphism of metabolites affected by AIBP deletion, with more statistically significant changes in the AIBP knockout female vs male when compared with the corresponding controls. AIBP knockout trends to reduce cholesterol but increase the bile acid precursor 7-HOCA in female but not male. Complex lipids, phospholipids, sphingomyelin and plasmalogens were reduced, while monoacylglycerol, fatty acids and the lipid soluble vitamins E and carotene diol were elevated in AIBP knockout female but not male. NAD metabolites were not significantly different in AIBP knockout vs control mice but differed for male vs female mice. Metabolites associated with glycolysis and the Krebs cycle were unchanged by AIBP knockout. Importantly, polyamine spermidine, critical for many cellular functions including cerebral cortex synapses, was reduced in male but not female AIBP knockout. This is the first report of a systemic metabolite profile of plasma samples from AIBP knockout mice, and provides a metabolic basis for future studies of AIBP regulation of cellular metabolism and the pathophysiological presentation of AIBP deficiency in patients.
新兴研究表明，载脂蛋白 A-I 结合蛋白（AIBP）是一种分泌蛋白，在细胞外发挥作用，促进细胞胆固醇外流，从而破坏质膜上的脂质筏。AIBP 也存在于线粒体中，作为差向异构酶发挥作用，促进功能失调的水合 NAD(P)H（称为 NAD(P)H(X)）的修复。重要的是，AIBP 缺乏导致致命的神经代谢紊乱，类似于人类的 Leigh 综合征。虽然循环 NADPHX 的产生被认为是潜在的原因，但我们假设非靶向代谢组学分析可能：1）揭示致死性的新线索，例如线粒体代谢物的变化，和 2）确定与 AIBP 新功能相关的代谢物。为此，我们对成年 AIBP 敲除小鼠和雌雄同笼对照的血浆进行了非靶向和深入的代谢组学研究。我们的系统代谢组学分析涵盖了 9 个超级途径，共鉴定出 640 种化合物。我们的研究表明，AIBP 缺失对代谢物的影响存在明显的性别二态性，与相应的对照相比，AIBP 敲除雌性的变化更为显著。与雄性相比，AIBP 敲除雌性的胆固醇降低，胆汁酸前体 7-HOCA 增加。复合脂质、磷脂、神经鞘磷脂和血浆类脂减少，而单酰甘油、脂肪酸以及脂溶性维生素 E 和胡萝卜二醇增加。NAD 代谢物在 AIBP 敲除与对照小鼠之间没有显著差异，但在雄性与雌性小鼠之间存在差异。糖酵解和三羧酸循环的代谢物不受 AIBP 敲除的影响。重要的是，多胺亚精胺对于包括大脑皮层突触在内的许多细胞功能至关重要，在雄性 AIBP 敲除小鼠中减少，但在雌性中没有减少。这是 AIBP 敲除小鼠血浆样本系统代谢组学分析的首次报道，为进一步研究 AIBP 对细胞代谢的调节以及 AIBP 缺乏症在患者中的病理生理表现提供了代谢基础。
