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J. Biol. Chem., Vol. 278, Issue 35, 33501-33518, August 29, 2003
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Mice Lacking Phosphatidylinositol Transfer Protein-
Exhibit Spinocerebellar Degeneration, Intestinal and Hepatic Steatosis, and Hypoglycemia*
¶ 
From the
Department of Cell and Developmental
Biology, Lineberger Comprehensive Cancer Center, University of North Carolina,
Chapel Hill, North Carolina 27599-7090, the
Department of Neurology, University of Michigan
School of Medicine, Ann Arbor Veterans Affairs Medical Center GRECC, Ann
Arbor, Michigan 48104-0520, the ||Department of
Nutrition, University of Alabama at Birmingham, Birmingham, Alabama 35294, and
**University of California School of Medicine, San
Diego, La Jolla, California 92093-0644
Phosphatidylinositol transfer proteins (PITPs) regulate the interface
between lipid metabolism and cellular functions. We now report that ablation
of PITP
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–/–
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 in with glucose homeostasis and in mammalian endoplasmic
reticulum functions that interface with transport of specific luminal lipid
cargoes.
Received for publication, April 7, 2003 , and in revised form, May 30, 2003.
* This work was supported in part by National Institutes of Health Grant NS37723 (to V. A. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
¶ Recipient of a National Institutes of Health grant.
To whom correspondence should be addressed. Tel.: 919-962-9870; Fax:
919-966-1856; E-mail:
vytas{at}med.unc.edu.
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