Alb James G, Phillips Scott E, Wilfley Lindsey R, Philpot Benjamin D, Bankaitis Vytas A
Department of Cell and Developmental Biology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7090, USA.
J Lipid Res. 2007 Aug;48(8):1857-72. doi: 10.1194/jlr.M700145-JLR200. Epub 2007 May 24.
Phosphatidylinositol transfer proteins (PITPs) bind phosphatidylinositol (PtdIns) and phosphatidylcholine and play diverse roles in coordinating lipid metabolism/signaling with intracellular functions. The underlying mechanisms remain unclear. Genetic ablation of PITPalpha in mice results in neonatal lethality characterized by intestinal and hepatic steatosis, spinocerebellar neurodegeneration, and glucose homeostatic defects. We report that mice expressing a PITPalpha selectively ablated for PtdIns binding activity (Pitpalpha(T59D)), as the sole source of PITPalpha, exhibit phenotypes that recapitulate those of authentic PITPalpha nullizygotes. Analyses of mice with graded reductions in PITPalpha activity reveal proportionately graded reductions in lifespan, demonstrate that intestinal steatosis and hypoglycemia are apparent only when PITPalpha protein levels are strongly reduced (>or=90%), and correlate steatotic and glucose homeostatic defects with cerebellar inflammatory disease. Finally, reconstitution of PITPalpha expression in the small intestine substantially corrects the chylomicron retention disease and cerebellar inflammation of Pitpalpha(0/0) neonates, but does not rescue neonatal lethality in these animals. These data demonstrate that PtdIns binding is an essential functional property of PITPalpha in vivo, and suggest a causal linkage between defects in lipid transport and glucose homeostasis and cerebellar inflammatory disease. Finally, the data also demonstrate intrinsic neuronal deficits in PITPalpha-deficient mice that are independent of intestinal lipid transport defects and hypoglycemia.
磷脂酰肌醇转移蛋白（PITPs）可结合磷脂酰肌醇（PtdIns）和磷脂酰胆碱，并在协调脂质代谢/信号传导与细胞内功能方面发挥多种作用。其潜在机制尚不清楚。小鼠中PITPα的基因敲除导致新生儿死亡，其特征为肠道和肝脏脂肪变性、脊髓小脑神经变性以及葡萄糖稳态缺陷。我们报告称，作为PITPα的唯一来源，表达选择性缺失PtdIns结合活性的PITPα（Pitpα（T59D））的小鼠表现出与真正的PITPα纯合子相同的表型。对PITPα活性分级降低的小鼠进行分析发现，寿命按比例分级降低，表明只有当PITPα蛋白水平大幅降低（≥90%）时，肠道脂肪变性和低血糖才会明显，并将脂肪变性和葡萄糖稳态缺陷与小脑炎性疾病相关联。最后，在小肠中重建PITPα表达可基本纠正Pitpα（0/0）新生儿的乳糜微粒滞留病和小脑炎症，但不能挽救这些动物的新生儿死亡。这些数据表明，PtdIns结合是PITPα在体内的一项基本功能特性，并提示脂质运输缺陷、葡萄糖稳态与小脑炎性疾病之间存在因果联系。最后，数据还表明PITPα缺陷小鼠存在内在神经元缺陷，这些缺陷与肠道脂质运输缺陷和低血糖无关。
