title: Mice lacking phosphatidylinositol transfer protein-alpha exhibit spinocerebellar degeneration, intestinal and hepatic steatosis, and hypoglycemia.
abstract: Phosphatidylinositol transfer proteins (PITPs) regulate the interface between lipid metabolism and cellular functions. We now report that ablation of PITP alpha function leads to aponecrotic spinocerebellar disease, hypoglycemia, and intestinal and hepatic steatosis in mice. The data indicate that hypoglycemia is in part associated with reduced proglucagon gene expression and glycogenolysis that result from pancreatic islet cell defects. The intestinal and hepatic steatosis results from the intracellular accumulation of neutral lipid and free fatty acid mass in these organs and suggests defective trafficking of triglycerides and diacylglycerols from the endoplasmic reticulum. We propose that deranged intestinal and hepatic lipid metabolism and defective proglucagon gene expression contribute to hypoglycemia in PITP alpha-/- mice, and that hypoglycemia is a significant contributing factor in the onset of spinocerebellar disease. Taken together, the data suggest an unanticipated role for PITP alpha in with glucose homeostasis and in mammalian endoplasmic reticulum functions that interface with transport of specific luminal lipid cargoes.
authors.affiliation: Department of Cell and Developmental Biology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599-7090, USA.
authors.forename: James G
authors.initials: JG
authors.lastname: Alb
authors.forename: Jorge D
authors.initials: JD
authors.lastname: Cortese
authors.forename: Scott E
authors.initials: SE
authors.lastname: Phillips
authors.forename: Roger L
authors.initials: RL
authors.lastname: Albin
authors.forename: Tim R
authors.initials: TR
authors.lastname: Nagy
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Hamilton
authors.forename: Vytas A
authors.initials: VA
authors.lastname: Bankaitis
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000196:embryology / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology*; D002531:Cerebellum / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D005822:Genetic Vectors; D005838:Genotype; D005934:Glucagon / Q000096:biosynthesis / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D007003:Hypoglycemia / Q000235:genetics* / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D007410:Intestinal Diseases / Q000235:genetics*; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D008107:Liver Diseases / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D008957:Models, Genetic; D010641:Phenotype; D049294:Phospholipid Transfer Proteins; D052336:Proglucagon; D011498:Protein Precursors / Q000096:biosynthesis / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins; D013132:Spinocerebellar Degenerations / Q000235:genetics*; D013997:Time Factors
chemical_list: D002352:Carrier Proteins; D005227:Fatty Acids; D008565:Membrane Proteins; D049294:Phospholipid Transfer Proteins; D011498:Protein Precursors; C118289:SEC24 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D052336:Proglucagon; D000255:Adenosine Triphosphate; D006003:Glycogen; D005934:Glucagon