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J. Biol. Chem., Vol. 282, Issue 43, 31592-31600, October 26, 2007

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Normal Flux through ATP-Citrate Lyase or Fatty Acid Synthase Is Not Required for Glucose-stimulated Insulin Secretion^*

Jamie W. Joseph, Matthew L. Odegaard, Sarah M. Ronnebaum, Shawn C. Burgess, Jeffrey Muehlbauer, A. Dean Sherry, and Christopher B. Newgard¹

From the Sarah W. Stedman Nutrition and Metabolism Center and Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27704 and the Ralph and Mary Nell Rogers NMR Center and Advanced Imaging Research Center, Departments of Radiology and Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75235

It has been proposed that de novo synthesis of long-chain acyl-CoA (LC-CoA) is a signal for glucose-stimulated insulin secretion (GSIS). Key enzymes involved in synthesis of fatty acids from glucose include ATP-citrate lyase (CL) and fatty acid synthase (FAS). An inhibitor of CL, hydroxycitrate (HC), has been reported to inhibit insulin secretion in some laboratories but not in others. Here we show that high concentrations of NaCl created during preparation of HC by standard methods explain the inhibition of GSIS, and that removal of the excess NaCl prevents the effect. To further investigate the role of CL, two small interfering RNA adenoviruses (Ad-siCL2 and Ad-siCL3) were generated. Ad-siCL3 reduced CL mRNA levels by 92 ± 6% and CL protein levels by 75 ± 4% but did not affect GSIS in 832/13 cells compared with cells treated with a control adenovirus (Ad-siControl). Similar results were obtained with Ad-siCL2. Ad-siCL3-treated cells also exhibited a 52 ± 7% reduction in cytosolic oxaloacetate, an 83 ± 4% reduction in malonyl-CoA levels, and inhibition of [U-¹⁴C]glucose incorporation into lipid by 43 ± 4%, all expected metabolic out-comes of CL suppression. Similarly, treatment of 832/13 cells with a recombinant adenovirus specific to FAS (Ad-siFAS) reduced FAS mRNA levels by 81 ± 2% in 832/13 cells, resulting in a 59 ± 4% decrease in [U-¹⁴C]glucose incorporation into lipid, without affecting GSIS. Finally, treatment of primary rat islets with Ad-siCL3 or Ad-siFAS reduced CL and FAS mRNA levels by 65 ± 4% and 52 ± 3%, respectively, but had no effect on GSIS relative to Ad-siControl-treated islets. These findings demonstrate that a normal rate of flux of glucose carbons through CL and FAS is not required for GSIS in insulinoma cell lines or rat islets.

Received for publication, July 24, 2007 , and in revised form, August 24, 2007.

^* The work was supported by a Canadian Institute of Health Research Fellow-ship (to J. W. J.) and National Institutes of Health Grants DK42583 and DK58398 (to C. B. N. and A. D. 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: Duke Independence Park Facility, 4321 Medical Park Dr., Suite 200, Durham, NC 27704. Tel.: 919-668-6059; Fax: 919-477-0632; E-mail: newga002{at}mc.duke.edu.

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