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J. Biol. Chem., Vol. 282, Issue 29, 21134-21144, July 20, 2007

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Specificity in Beta Cell Expression of L-3-Hydroxyacyl-CoA Dehydrogenase, Short Chain, and Potential Role in Down-regulating Insulin Release^*

Geert A. Martens, Annelies Vervoort, Mark Van de Casteele, Geert Stangé, Karine Hellemans, Hong Vien Van Thi, Frans Schuit^¶, and Daniël Pipeleers¹

From the Diabetes Research Center, Brussels Free University-VUB, Laarbeeklaan 103, B-1090 Brussels, the Laboratory of Pediatrics, Brugmann Hospital, Brussels Free University-ULB, B-1020 Brussels, and the ^¶Gene Expression Unit, Department of Molecular Cell Biology, Katholieke Universiteit Leuven-KUL, B-3000 Leuven, Belgium

A loss-of-function mutation of the mitochondrial -oxidation enzyme L-3-hydroxyacyl-CoA dehydrogenase, short chain (HADHSC), has been associated with hyperinsulinemic hypoglycemia in man. It is still unclear whether loss of glucose homeostasis in these patients (partly) results from a dysregulation of beta cells. This study examines HADHSC expression in purified rat beta cells and investigates whether its selective suppression elevates insulin release. Beta cells expressed the highest levels of HADHSC mRNA and protein of all examined tissues, including those with high rates of mitochondrial -oxidation. On the other hand, beta cells expressed relatively low levels of other -oxidation enzymes (acyl-CoA dehydrogenase short, medium, and long chain and acetyl-coenzyme A acyltransferase 2). HADHSC expression was sequence-specifically silenced by RNA interference, and the effects were examined on glucose-stimulated insulin secretion following 48–72 h of suppression. In both rat beta cells and in the beta cell line INS1 832-13, HADHSC silencing resulted in elevated insulin release at low and at high glucose concentrations, which appeared not to be caused by increased rates of glucose metabolism or an inhibition in fatty acid oxidation. These data indicate that the normal beta cell phenotype is characterized by a high expression of HADHSC and a low expression of other -oxidation enzymes. Down-regulation of HADHSC causes an elevated secretory activity suggesting that this enzyme protects against inappropriately high insulin levels and hypoglycemia.

Received for publication, January 3, 2007 , and in revised form, April 13, 2007.

^* This work was supported by the Research Foundation Flanders (FWO-Vlaanderen) Grants G.0357.03 (to D. P.) and G.0529.05 (to F. S. and D. P.), a Ph.D. fellowship (to G. A. M.), and by the Inter-University Poles of Attraction Program IUAP P5/17 from the Belgian Science Policy. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ To whom correspondence should be addressed. Tel.: 32-2-4774541; Fax: 32-2-4774545; E-mail: Daniel.Pipeleers{at}vub.ac.be.

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