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J. Biol. Chem., Vol. 279, Issue 53, 55946-55957, December 31, 2004

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Increased Phosphatidylcholine Production but Disrupted Glycogen Metabolism in Fetal Type II Cells of Mice That Overexpress CTP:Phosphocholine Cytidylyltransferase^*

Ross Ridsdale, Irene Tseu, Matthias Roth-Kleiner, Jinxia Wang, and Martin Post

From the Canadian Institutes of Health Research Group in Lung Development, Hospital for Sick Children Research Institute and Institute of Medical Sciences, University of Toronto, Toronto, M5G 1X8 Canada

CTP:phosphocholine cytidylyltransferase (CCT) is a rate-determining enzyme in the de novo synthesis of phosphatidylcholine (PtdCho). Alveolar type II cells synthesize large quantities of disaturated PtdCho, the surface-active agent of pulmonary surfactant, particularly at late gestation when the lung prepares itself for postnatal air breathing. To clarify the role of CCT in lung surfactant maturation, we overexpressed CCT^1-367 using the surfactant protein-C promoter. Lungs of transgenic mice were analyzed at day 18 of gestation (term = 19 days). Overexpression of CCT^1-367 increased the synthesis and content of PtdCho in fetal type II cells isolated from the transgenic mice. Also, PtdCho content of fetal lung fluid was increased. No changes in surfactant protein content were detected. Interestingly, fetal type II cells of transgenic mice contained more glycogen than control cells. Incorporation studies with [U-¹⁴C]glucose demonstrated that overexpression of CCT^1-367 in fetal type II cells increased glycogen synthesis without affecting glycogen breakdown. To determine which domain contributes to this glycogen phenotype, two additional transgenes were created overexpressing either CCT^1-239 or CCT^239-367. Glycogen synthesis and content were increased in fetal type II cells expressing CCT^239-367 but not CCT^1-239_. We conclude that overexpression of CCT increases surfactant PtdCho synthesis without affecting surfactant protein levels but that it disrupts glycogen metabolism in differentiating type II cells via its regulatory domain.

Received for publication, July 8, 2004 , and in revised form, October 1, 2004.

^* 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.

To whom correspondence should be addressed: Division of Lung Biology, Hospital for Sick Children, 555 University Ave., Toronto, Ontario M5G 1X8, Canada. Tel.: 416-813-6772; Fax: 416-813-5002; E-mail: martin.post{at}sickkids.ca.

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