[Show abstract][Hide abstract] ABSTRACT: Phosphatidylinositol transfer proteins (PITPs) regulate the interface between lipid metabolism and cellular functions, but the fundamental nature of this regulation is not understood. To address these questions in mammals, we generated mice nullizygous for various PITP isoforms. Ablation of murine PITPα function leads to aponecrotic spinocerebellar disease, hypoglycemia, and intestinal and hepatic steatosis. The conditions of steatosis suggest defective biogenesis and trafficking of lipoproteins from the endoplasmic reticulum into the circulation. The hypoglycemia is associated with reduced numbers and general compromise of pancreatic islets. These defects lead to reduced proglucagon gene expression and inappropriate channeling of glucose into glycogen stores. The available data indicate hypoglycemia is a major contributing factor in determining rate of onset of spinocerebellar disease. The collective data suggest an unanticipated role for PITPα in mammalian endoplasmic reticulum functions involved in the packaging and transport of specific lumenal lipid cargos.
No preview · Article · Feb 2004 · Advances in Enzyme Regulation
[Show abstract][Hide abstract] 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.
No preview · Article · Sep 2003 · Journal of Biological Chemistry