The pathologies associated with functional titration of phosphatidylinositol transfer protein a activity in mice
The pathologies associated with functional titration of phosphatidylinositol transfer protein a activity in mice
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DOI：
10.1194/jlr.m700145-jlr200
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发表时间：
2007-08-01
影响因子：
6.5
通讯作者：
Bankaitis, Vytas A.
中科院分区：
文献类型：
--
作者：
Alb, James G., Jr.;Phillips, Scott E.;Bankaitis, Vytas A.
磷脂酰肌醇转移蛋白（PITP）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中发挥多种作用。其潜在机制尚不清楚。小鼠中PITP α的基因消融会导致新生儿死亡，其特征是肠道和肝脏脂肪变性、脊髓小脑神经变性和葡萄糖稳态缺陷。我们报告说，小鼠表达的PITPa选择性消融PtdIns结合活性（Pitpa（T59 D）），作为唯一的来源PITPa，表现出的表型，重演那些真实的PITPa nulliozygotes。对PITPa活性分级降低的小鼠的分析揭示了寿命的成比例分级降低，证明了肠脂肪变性和低血糖症仅在PITPa蛋白水平强烈降低（>= 90%）时才明显，并且脂肪变性和葡萄糖稳态缺陷与小脑炎性疾病相关。最后，小肠中PITPa表达的重建基本上纠正了Pitpa（0/0）新生儿的乳糜微粒潴留疾病和小脑炎症，但不能挽救这些动物的新生儿死亡率。这些数据表明，PtdIns结合是体内PITPa的基本功能特性，并表明脂质转运和葡萄糖稳态缺陷与小脑炎性疾病之间存在因果关系。最后，这些数据还证明了PITP α缺陷小鼠的内在神经元缺陷，其独立于肠脂质转运缺陷和低血糖。
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 PITP alpha in mice results in neonatal lethality characterized by intestinal and hepatic steatosis, spinocerebellar neurodegeneration, and glucose homeostatic defects. We report that mice expressing a PITPa selectively ablated for PtdIns binding activity (Pitpa(T59D)), as the sole source of PITPa, exhibit phenotypes that recapitulate those of authentic PITPa nullizygotes. Analyses of mice with graded reductions in PITPa activity reveal proportionately graded reductions in lifespan, demonstrate that intestinal steatosis and hypoglycemia are apparent only when PITPa protein levels are strongly reduced (>= 90%), and correlate steatotic and glucose homeostatic defects with cerebellar inflammatory disease. Finally, reconstitution of PITPa expression in the small intestine substantially corrects the chylomicron retention disease and cerebellar inflammation of Pitpa(0/0) neonates, but does not rescue neonatal lethality in these animals. These data demonstrate that PtdIns binding is an essential functional property of PITPa 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 PITP alpha-deficient mice that are independent of intestinal lipid transport defects and hypoglycemia.