ArticleMolecular metabolism2016
Knockdown of ATP citrate lyase in pancreatic beta cells does not inhibit insulin secretion or glucose flux and implicates the acetoacetate pathway in insulin secretion.
Article in Molecular metabolism, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 28 citations in OpenAlex.
- Mitochondria as Epigenetic Regulators of β-Cell Identity and Plasticity: A Metabolo-Epigenetic Perspective.Cells · 2026Review
- The Dual Anaplerotic Model (DAM): Integral Roles of Pyruvate Carboxylase and the GABA Shunt in Beta Cell Insulin Secretion.Life (Basel, Switzerland) · 2026Article
- β‑hydroxybutyric acid as a potential therapeutic metabolite for type 2 diabetes mellitus (Review).International journal of molecular medicine · 2026Review
- Empagliflozin improves mitochondrial dysfunction in diabetic cardiomyopathy by modulating ketone body metabolism and oxidative stress.Redox biology · 2024Article
- Metabolic cycles and signals for insulin secretion.Cell metabolism · 2022Review
- Contribution of Mitochondria to Insulin Secretion by Various Secretagogues.Antioxidants & redox signaling · 2022Review
- Emerging Role of Hepatic Ketogenesis in Fatty Liver Disease.Frontiers in physiology · 2022Review
- The Pancreatic β-Cell: The Perfect Redox System.Antioxidants (Basel, Switzerland) · 2021Review
- Epigenetic Regulation of TLR4 in Diabetic Macrophages Modulates Immunometabolism and Wound Repair.Journal of immunology (Baltimore, Md. : 1950) · 2020Article
- Factors Influencing Mitochondrial Function as a Key Mediator of Glucose-Induced Insulin Release: Highlighting Nicotinamide Nucleotide Transhydrogenase.International journal of molecular and cellular medicine · 2020Review
- Review
- The vital role of ATP citrate lyase in chronic diseases.Journal of molecular medicine (Berlin, Germany) · 2020Review
- Disruption of beta cell acetyl-CoA carboxylase-1 in mice impairs insulin secretion and beta cell mass.Diabetologia · 2019Article
- Mechanisms of the amplifying pathway of insulin secretion in the β cell.Pharmacology & therapeutics · 2017Review
- Comparative metabolomics study on therapeutic mechanism of electro-acupuncture and moxibustion on rats with chronic atrophic gastritis (CAG).Scientific reports · 2017Article
- Dimethyl Itaconate Is Not Metabolized into Itaconate Intracellularly.The Journal of biological chemistry · 2017Article
- Multi-dimensional Roles of Ketone Bodies in Fuel Metabolism, Signaling, and Therapeutics.Cell metabolism · 2017Review
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
objectiveGlucose-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.
methodsWe 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.
resultsIn both instances glucose-stimulated insulin release was not inhibited. Mass spectrometry analysis showed that the flux of carbon from [U-(13)C]glucose and/or [U-(13)C]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 (13)C-glucose and (13)C-KIC introduced substantial (13)C 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.
conclusionThe results establish the involvement of the acetoacetate pathway in insulin secretion in pancreatic beta cells.
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