The pathologies associated with functional titration of phosphatidylinositol transfer protein a activity in mice

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.