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J. Biol. Chem., Vol. 282, Issue 49, 35657-35665, December 7, 2007

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A Role for ATP-Citrate Lyase, Malic Enzyme, and Pyruvate/Citrate Cycling in Glucose-induced Insulin Secretion^*

From the Molecular Nutrition Unit and the Montreal Diabetes Research Center, the Centre de Recherche du Centre Hospitalier de l'Université de Montréal and the Departments of Nutrition and Biochemistry, University of Montreal, Montreal, Quebec H1W 4A4, Canada

In pancreatic β-cells, metabolic coupling factors generated during glucose metabolism and pyruvate cycling through anaplerosis/cataplerosis processes contribute to the regulation of insulin secretion. Pyruvate/citrate cycling across the mitochondrial membrane leads to the production of malonyl-CoA and NADPH, two candidate coupling factors. To examine the implication of pyruvate/citrate cycling in glucose-induced insulin secretion (GIIS), different steps of the cycle were inhibited in INS 832/13 cells by pharmacological inhibitors and/or RNA interference (RNAi) technology: mitochondrial citrate export, ATP-citrate lyase (ACL), and cytosolic malic enzyme (ME1). The inhibitors of the di- and tri-carboxylate carriers, n-butylmalonate and 1,2,3-benzenetricarboxylate, respectively, reduced GIIS, indicating the importance of transmitochondrial transport of tri- and dicarboxylates in the action of glucose. To directly test the role of ACL and ME1 in GIIS, small hairpin RNA (shRNA) were used to selectively decrease ACL or ME1 expression in transfected INS 832/13 cells. shRNA-ACL reduced ACL protein levels by 67%, and this was accompanied by a reduction in GIIS. The amplification/K_ATP-independent pathway of GIIS was affected by RNAi knockdown of ACL. The ACL inhibitor radicicol also curtailed GIIS. shRNA-ME1 reduced ME1 activity by 62% and decreased GIIS. RNAi suppression of either ACL or ME1 did not affect glucose oxidation. However, because ACL is required for malonyl-CoA formation, inhibition of ACL expression by shRNA-ACL decreased glucose incorporation into palmitate and increased fatty acid oxidation in INS 832/13 cells. Taken together, the results underscore the importance of pyruvate/citrate cycling in pancreatic β-cell metabolic signaling and the regulation of GIIS.

Received for publication, August 30, 2007 , and in revised form, October 3, 2007.

^* This work was supported in part by a grant from the Canadian Institute of Health Research (to M. P.). 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 Supported by graduate studentships from the Fonds de Recherche en Santé du Québec and Programmes de Biologie Moléculaire de l'Universitéde Montréal.

² To whom correspondence should be addressed: MDRC-CR-CHUM, Technopole Angus, Rm. 401, 2901, Rachel St., Montreal, QC H1W 4A4, Canada. Tel.: 514-890-8000 (ext. 23642) Fax: 514-412-7648; E-mail: marc.prentki{at}umontreal.ca.

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