title: The pathologies associated with functional titration of phosphatidylinositol transfer protein alpha activity in mice.
abstract: 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 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 PITPalpha nullizygotes. Analyses of mice with graded reductions in PITPalpha activity reveal proportionately graded reductions in lifespan, demonstrate that intestinal steatosis and hypoglycemia are apparent only when PITPalpha protein levels are strongly reduced (>or=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. These data demonstrate that PtdIns binding is an essential functional property of PITPalpha 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.
authors.affiliation: Department of Cell and Developmental Biology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7090, USA.
authors.forename: James G
authors.initials: JG
authors.lastname: Alb
authors.forename: Scott E
authors.initials: SE
authors.lastname: Phillips
authors.forename: Lindsey R
authors.initials: LR
authors.lastname: Wilfley
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Philpot
authors.forename: Vytas A
authors.initials: VA
authors.lastname: Bankaitis
mesh_terms: D000483:Alleles; D000818:Animals; D001665:Binding Sites; D002526:Cerebellar Diseases / Q000378:metabolism / Q000473:pathology; D002531:Cerebellum / Q000378:metabolism; D005234:Fatty Liver / Q000378:metabolism / Q000473:pathology; D005260:Female; D005947:Glucose / Q000378:metabolism; D007410:Intestinal Diseases / Q000378:metabolism / Q000473:pathology; D007421:Intestine, Small / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008957:Models, Genetic; D019636:Neurodegenerative Diseases / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D010716:Phosphatidylinositols / Q000378:metabolism; D049294:Phospholipid Transfer Proteins / Q000235:genetics / Q000378:metabolism*; D009435:Synaptic Transmission
chemical_list: D010716:Phosphatidylinositols; D049294:Phospholipid Transfer Proteins; C493468:Pitpn protein, mouse; D005947:Glucose