Feasibility of pathways for transfer of acyl groups from mitochondria to the cytosol to form short chain acyl-CoAs in the pancreatic beta cell

Childrens Diabetes Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53706, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 11/2007; 282(42):30596-606. DOI: 10.1074/jbc.M702732200
Source: PubMed


The mitochondria of pancreatic beta cells are believed to convert insulin secretagogues into products that are translocated to the cytosol where they participate in insulin secretion. We studied the hypothesis that short chain acyl-CoA (SC-CoAs) might be some of these products by discerning the pathways of SC-CoA formation in beta cells. Insulin secretagogues acutely stimulated 1.5-5-fold increases in acetoacetyl-CoA, succinyl-CoA, malonyl-CoA, hydroxymethylglutaryl-CoA (HMG-CoA), and acetyl-CoA in INS-1 832/13 cells as judged from liquid chromatography-tandem mass spectrometry measurements. Studies of 12 relevant enzymes in rat and human pancreatic islets and INS-1 832/13 cells showed the feasibility of at least two redundant pathways, one involving acetoacetate and the other citrate, for the synthesis SC-CoAs from secretagogue carbon in mitochondria and the transfer of their acyl groups to the cytosol where the acyl groups are converted to SC-CoAs. Knockdown of two key cytosolic enzymes in INS-1 832/13 cells with short hairpin RNA supported the proposed scheme. Lowering ATP citrate lyase 88% did not inhibit glucose-induced insulin release indicating citrate is not the only carrier of acyl groups to the cytosol. However, lowering acetoacetyl-CoA synthetase 80% partially inhibited glucose-induced insulin release indicating formation of SC-CoAs from acetoacetate in the cytosol is important for insulin secretion. The results indicate beta cells possess enzyme pathways that can incorporate carbon from glucose into acetyl-CoA, acetoacetyl-CoA, and succinyl-CoA and carbon from leucine into these three SC-CoAs plus HMG-CoA in their mitochondria and enzymes that can form acetyl-CoA, acetoacetyl-CoA, malonyl-CoA, and HMG-CoA in their cytosol.

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Available from: Noaman M Hasan, May 27, 2014
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    • "Impact of the siRNA Delivery Methods on Insulin Secretion – The RNAi technology has been used to investigate the role of anaplerosis and pyruvate cycling processes in GIIS [24], [25], [26], [27], [32], [38], [39], [40], [53], [54]. Normal ß-cells and INS 832/13 ß-cells are difficult to transfect and therefore earlier studies generally used adenoviral vectors to deliver RNAi or cDNA into normal rodent islet cells as well as in INS1 cells and INS 832/13 cells. "
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    • "ACLY is most abundantly expressed in the liver and white adipose tissue [2] [3] while it exhibits low expression levels in brain, heart, small intestine and muscles [2] [4]. ACLY is also expressed and active in pancreatic beta cells [3] [5]. Additionally, over-expression of ACLY is associated with certain pathological conditions that will be discussed later in this article. "
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