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A more recent version of this article appeared on August 1, 2007

Papers In Press, published online ahead of print May 24, 2007
J. Lipid Res., doi:10.1194/jlr.M700145-JLR200
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Submitted on March 23, 2007
Revised on May 11, 2007
Accepted on May 24, 2007

Functional dissection of the relationships between phosphatidylinositol transfer protein alpha activity and the complex pathologies of PITPalpha nullizygous mice

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

Cell & Developmental Biology, University of North Carolina, School of Medicine, Chapel Hill, NC 27599-7090

Corresponding Author: vytas{at}med.unc.edu

Phosphatidylinositol transfer proteins (PITPs) bind phosphatidylinositol (PtdIns) and phosphatidylcholine (PtdCho),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 PITP-nullizygotes. Analyses of mice with graded reductions in PITPalpha activity report proportionately graded reductions in lifespan, demonstrate that intestinal steatosis and hypoglycemia are apparent only when PITPalpha protein levels are strongly reduced (>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. The data demonstrate PtdIns-binding is an essential functional property of PITP{alpha 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.


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[Abstract] [Full Text] [PDF]


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