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J. Biol. Chem., Vol. 283, Issue 20, 13538-13548, May 16, 2008

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Protection from High Fat Diet-induced Increase in Ceramide in Mice Lacking Plasminogen Activator Inhibitor 1^*

Charmi Shah, Guang Yang, Ian Lee, Jacek Bielawski, Yusuf A. Hannun, and Fahumiya Samad¹

From the Torrey Pines Institute for Molecular Studies, San Diego, California 92121 and the Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425

Obesity increases the risk for metabolic and cardiovascular disease, and adipose tissue plays a central role in this process. Ceramide, the key intermediate of sphingolipid metabolism, also contributes to obesity-related disorders. We show that a high fat diet increased ceramide levels in the adipose tissues and plasma in C57BL/6J mice via a mechanism that involves an increase in gene expression of enzymes mediating ceramide generation through the de novo pathway (e.g. serine palmitoyltransferase) and via the hydrolysis of sphingomyelin (acid sphingomyelinase and neutral sphingomyelinase). Although the induction of total ceramide in response to the high fat diet was modest, dramatic increases were observed for C16, C18, and C18:1 ceramides. Next, we investigated the relationship of ceramide to plasminogen activator inhibitor-1 (PAI-1), the primary inhibitor of plasminogen activation and another key player in obesity. PAI-1 is consistently elevated in obesity and thought to contribute to increased artherothrombotic events and more recently to obesity-mediated insulin resistance. Interestingly, the changes in ceramide were attenuated in mice lacking PAI-1. Mechanistically, mice lacking PAI-1 were protected from diet-induced increase in serine palmitoyltransferase, acid sphingomyelinase, and neutral sphingomyelinase mRNA, providing a mechanistic link for decreased ceramide in PAI-1^–/– mice. The decreases in plasma free fatty acids and adipose tumor necrosis factor- in PAI-1^–/– mice may have additionally contributed indirectly to improvements in ceramide profile in these mice. This study has identified a novel link between sphingolipid metabolism and PAI-1 and also suggests that ceramide may be an intermediary molecule linking elevated PAI-1 to insulin resistance.

Received for publication, December 5, 2007 , and in revised form, February 29, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant R01HL071146 (to F. S.). 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.

¹ To whom correspondence should be addressed: Torrey Pines Institute for Molecular Studies, San Diego, CA 92121. Tel.: 858-455-3812; Fax: 858-909-5060; E-mail: fsamad{at}tpims.org.

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This article has been cited by other articles:

				G. Yang, L. Badeanlou, J. Bielawski, A. J. Roberts, Y. A. Hannun, and F. Samad Central role of ceramide biosynthesis in body weight regulation, energy metabolism, and the metabolic syndrome Am J Physiol Endocrinol Metab, July 1, 2009; 297(1): E211 - E224. [Abstract] [Full Text] [PDF]