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Supplement

The Role of Long-Chain Fatty Acyl-CoA Esters in ß-Cell Signal Transduction^{1 ,2}

Barbara E. Corkey^*,3, Jude T. Deeney^*, Gordon C. Yaney^*, Keith Tornheim and Marc Prentki^**

^* Obesity Research Center, Departments of Medicine and Biochemistry, Boston University Medical School, Boston, MA 02118 and ^** Molecular Nutrition Unit, Department of Nutrition, University of Montreal and the CR-CHUM and Institut du Cancer, Montreal, QC, Canada H2L 4M1

³To whom correspondence should be addressed.

Glucose-induced insulin secretion is associated with inhibition of free fatty acid (FFA) oxidation, increased esterification and complex lipid formation by pancreatic ß-cells. Abundant evidence favors a role for cytosolic long-chain acyl-CoA (LC-CoA), including the rapid rise in malonyl CoA, the inhibitory effect of hydroxycitrate or acetyl CoA carboxylase knockout, both of which prevent malonyl CoA formation, and the stimulatory effect of exogenous FFA. On the other hand, some evidence opposes the concept, including the fall in total LC-CoA levels in response to glucose, the stimulatory effect of LC-CoA on K_ATP channels and the lack of inhibition of glucose-stimulated secretion either by overexpression of malonyl CoA decarboxylase, which markedly lowers malonyl CoA levels, or by triacsin C, which blocks FFA conversion to LC-CoA. Alternative explanations for these data are presented. A revised model of nutrient-stimulated secretion involving two arms of signal transduction that occur simultaneously is proposed. One arm depends on modulation of the K_ATP channel evoked by changes in the ATP/ADP ratio. The other arm depends upon anaplerotic input into the tricarboxylic acid cycle, generation of excess citrate, and increases in cytosolic malonyl-CoA. Input from this arm is increased LC-CoA. Signaling through both arms would be required for normal secretion. LC-CoA esters and products formed from them are potent regulators of enzymes and channels. It is hypothesized that their elevations directly modulate the activity of enzymes, genes and various ß-cell functions or modify the acylation state of key proteins involved in regulation of ion channels and exocytosis.

KEY WORDS: • long chain acyl CoA • insulin secretion • malonyl CoA • ATP-sensitive K⁺-channel • triascin C • free fatty acids • ATP/ADP ratio • B-cell

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