The pathologies associated with functional titration of phosphatidylinositol transfer protein α 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 mech- anisms remain unclear. Genetic ablation of PITPa in mice results in neonatal lethality characterized by intestinal and hepatic steatosis, spinocerebellar neurodegeneration, and glucose homeostatic defects. We report that mice express- ing a PITPa selectively ablated for PtdIns binding activity (Pitpa T59D ), as the sole source of PITPa, exhibit pheno- types that recapitulate those of authentic PITPa nullizygotes. Analyses of mice with graded reductions in PITPa activity reveal proportionately graded reductions in lifespan, dem- onstrate that intestinal steatosis and hypoglycemia are ap- parent only when PITPa protein levels are strongly reduced (>90%), and correlate steatotic and glucose homeostatic defects with cerebellar inflammatory disease. Finally, recon- stitution of PITPa expression in the small intestine sub- stantially 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 be- tween defects inlipidtransport and glucosehomeostasis and cerebellar inflammatory disease. Finally, the data also dem- onstrate intrinsic neuronal deficits in PITPa-deficient mice that are independent of intestinal lipidtransport defects and hypoglycemia.—Alb, J. G., Jr., S. E. Phillips, L. R. Wilfley, B. D. Philpot, and V. A. Bankaitis.Thepathologiesassociated with functional titration of phosphatidylinositol transfer pro- tein a activity in mice. J. Lipid Res. 2007. 48: 1857-1872.