Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 278, Issue 35, Pages 33501-33518Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M303591200
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Funding
- NIDDK NIH HHS [DK56350, P30 DK056350] Funding Source: Medline
- NIGMS NIH HHS [R01 GM086912] Funding Source: Medline
- NIMH NIH HHS [R01 MH059207] Funding Source: Medline
- NINDS NIH HHS [R56 NS037723, NS37723, R01 NS037723] Funding Source: Medline
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Phosphatidylinositol transfer proteins (PITPs) regulate the interface between lipid metabolism and cellular functions. We now report that ablation of PITPalpha 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 PITPalpha(-/-) mice, and that hypoglycemia is a significant contributing factor in the onset of spinocerebellar disease. Taken together, the data suggest an unanticipated role for PITPalpha in with glucose homeostasis and in mammalian endoplasmic reticulum functions that interface with transport of specific luminal lipid cargoes.
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