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Journal of Lipid Research, Vol. 48, 1857-1872, August 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

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

James G. Alb, Jr.^*, Scott E. Phillips^*, Lindsey R. Wilfley, Benjamin D. Philpot^,,** and Vytas A. Bankaitis^1,*

^* Department of Cell and Developmental Biology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7090
Department of Cell and Molecular Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7090
Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7090
^** Neurobiology Curriculum, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7090

Published, JLR Papers in Press, May 24, 2007.

¹ To whom correspondence should be addressed. e-mail: vytas{at}med.unc.edu

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 in mice results in neonatal lethality characterized by intestinal and hepatic steatosis, spinocerebellar neurodegeneration, and glucose homeostatic defects. We report that mice expressing a PITP selectively ablated for PtdIns binding activity (Pitp^T59D), as the sole source of PITP, exhibit phenotypes that recapitulate those of authentic PITP nullizygotes. Analyses of mice with graded reductions in PITP activity reveal proportionately graded reductions in lifespan, demonstrate that intestinal steatosis and hypoglycemia are apparent only when PITP protein levels are strongly reduced (90%), and correlate steatotic and glucose homeostatic defects with cerebellar inflammatory disease. Finally, reconstitution of PITP expression in the small intestine substantially corrects the chylomicron retention disease and cerebellar inflammation of Pitp^0/0 neonates, but does not rescue neonatal lethality in these animals. These data demonstrate that PtdIns binding is an essential functional property of PITP 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-deficient mice that are independent of intestinal lipid transport defects and hypoglycemia.

Supplementary key words signaling • phospholipids • lipoproteins • neurodegeneration

Abbreviations: CRD, chylomicron retention disease; ER, endoplasmic reticulum; EtOH, ethanol; fEPSP, field excitatory postsynaptic potential; GFAP, glial fibrillary acidic protein; MAMA, mismatch amplification mutation assay; PAC, P1 artificial chromosome; PITP, phosphatidylinositol transfer protein; PtdCho, phosphatidylcholine; PtdIns, phosphatidylinositol; TG, triglyceride

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