| Autor: |
Mahmoud El Azzouny, Melissa J. Longacre, Israr-ul H. Ansari, Robert T. Kennedy, Charles F. Burant, Michael J. MacDonald |
| Jazyk: |
angličtina |
| Rok vydání: |
2016 |
| Předmět: |
|
| Zdroj: |
Molecular Metabolism, Vol 5, Iss 10, Pp 980-987 (2016) |
| Druh dokumentu: |
article |
| ISSN: |
2212-8778 |
| DOI: |
10.1016/j.molmet.2016.07.011 |
| Popis: |
Objective: Glucose-stimulated insulin secretion in pancreatic beta cells requires metabolic signals including the generation of glucose-derived short chain acyl-CoAs in the cytosol from mitochondrially-derived metabolites. One concept of insulin secretion is that ATP citrate lyase generates short chain acyl-CoAs in the cytosol from mitochondrially-derived citrate. Of these, malonyl-CoA, is believed to be an important signal in insulin secretion. Malonyl-CoA is also a precursor for lipids. Our recent evidence suggested that, in the mitochondria of beta cells, glucose-derived pyruvate can be metabolized to acetoacetate that is exported to the cytosol and metabolized to the same short chain acyl-CoAs and fatty acids that can be derived from citrate. We tested for redundancy of the citrate pathway. Methods: We inhibited ATP citrate lyase activity using hydroxycitrate as well as studying a stable cell line generated with shRNA knockdown of ATP citrate lyase in the pancreatic beta cell line INS-1 832/13. Results: In both instances glucose-stimulated insulin release was not inhibited. Mass spectrometry analysis showed that the flux of carbon from [U-13C]glucose and/or [U-13C]α-ketoisocaproic acid (KIC) into short chain acyl-CoAs in cells with hydroxycitrate-inhibited ATP citrate lyase or in the cell line with stable severe (>90%) shRNA knockdown of ATP citrate lyase was similar to the controls. Both 13C-glucose and 13C-KIC introduced substantial 13C labeling into acetyl-CoA, malonyl-CoA, and HMG-CoA under both conditions. Glucose flux into fatty acids was not affected by ATP citrate lyase knockdown. Conclusion: The results establish the involvement of the acetoacetate pathway in insulin secretion in pancreatic beta cells. Keywords: Acetoacetate pathway, Malonyl-CoA, Acetyl-CoA, Palmitate, Mass spectrometry, Mitochondrial biosynthesis, Citrate |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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