Acetyl-CoA-carboxylase 1 (ACC1) plays a critical role in glucagon secretion.
View / Open Files
Authors
Denwood, Geoffrey
Liu, Dong
Morfin, Valentin
Vetterli, Laurène
Yonova-Doing, Ekaterina
Ahnfelt-Rønne, Jonas
Publication Date
2022-03-18Journal Title
Commun Biol
ISSN
2399-3642
Publisher
Springer Science and Business Media LLC
Volume
5
Issue
1
Number
ARTN 238
Pages
238
Type
Article
This Version
VoR
Physical Medium
Electronic
Metadata
Show full item recordCitation
Veprik, A., Denwood, G., Liu, D., Bany Bakar, R., Morfin, V., McHugh, K., Tebeka, N. N., et al. (2022). Acetyl-CoA-carboxylase 1 (ACC1) plays a critical role in glucagon secretion.. Commun Biol, 5 (1. ARTN 238), 238. https://doi.org/10.1038/s42003-022-03170-w
Abstract
Dysregulated glucagon secretion from pancreatic alpha-cells is a key feature of type-1 and type-2 diabetes (T1D and T2D), yet our mechanistic understanding of alpha-cell function is underdeveloped relative to insulin-secreting beta-cells. Here we show that the enzyme acetyl-CoA-carboxylase 1 (ACC1), which couples glucose metabolism to lipogenesis, plays a key role in the regulation of glucagon secretion. Pharmacological inhibition of ACC1 in mouse islets or αTC9 cells impaired glucagon secretion at low glucose (1 mmol/l). Likewise, deletion of ACC1 in alpha-cells in mice reduced glucagon secretion at low glucose in isolated islets, and in response to fasting or insulin-induced hypoglycaemia in vivo. Electrophysiological recordings identified impaired KATP channel activity and P/Q- and L-type calcium currents in alpha-cells lacking ACC1, explaining the loss of glucose-sensing. ACC-dependent alterations in S-acylation of the KATP channel subunit, Kir6.2, were identified by acyl-biotin exchange assays. Histological analysis identified that loss of ACC1 caused a reduction in alpha-cell area of the pancreas, glucagon content and individual alpha-cell size, further impairing secretory capacity. Loss of ACC1 also reduced the release of glucagon-like peptide 1 (GLP-1) in primary gastrointestinal crypts. Together, these data reveal a role for the ACC1-coupled pathway in proglucagon-expressing nutrient-responsive endocrine cell function and systemic glucose homeostasis.
Keywords
Acetyl Coenzyme A, Acetyl-CoA Carboxylase, Animals, Glucagon, Glucagon-Secreting Cells, Glucose, Insulin-Secreting Cells, Mice
Sponsorship
Medical Research Council (MC_UU_12012/3)
Identifiers
External DOI: https://doi.org/10.1038/s42003-022-03170-w
This record's URL: https://www.repository.cam.ac.uk/handle/1810/336592
Statistics
Total file downloads (since January 2020). For more information on metrics see the
IRUS guide.
Recommended or similar items
The current recommendation prototype on the Apollo Repository will be turned off on 03 February 2023. Although the pilot has been fruitful for both parties, the service provider IKVA is focusing on horizon scanning products and so the recommender service can no longer be supported. We recognise the importance of recommender services in supporting research discovery and are evaluating offerings from other service providers. If you would like to offer feedback on this decision please contact us on: support@repository.cam.ac.uk