Dowsett, L. , Duluc, L., Higgins, E., Alghamdi, F., Fast, W., Salt, I. P. and Leiper, J. (2023) Asymmetric dimethylarginine positively modulates calcium-sensing receptor signalling to promote lipid accumulation. Cellular Signalling, 107, 110676. (doi: 10.1016/j.cellsig.2023.110676) (PMID:37028778)
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Abstract
Asymmetric dimethylarginine (ADMA) is generated through the irreversible methylation of arginine residues. It is an independent risk factor for cardiovascular disease, currently thought to be due to its ability to act as a competitive inhibitor of the nitric oxide (NO) synthase enzymes. Plasma ADMA concentrations increase with obesity and fall following weight loss; however, it is unknown whether they play an active role in adipose pathology. Here, we demonstrate that ADMA drives lipid accumulation through a newly identified NO-independent pathway via the amino-acid sensitive calcium-sensing receptor (CaSR). ADMA treatment of 3T3-L1 and HepG2 cells upregulates a suite of lipogenic genes with an associated increase in triglyceride content. Pharmacological activation of CaSR mimics ADMA while negative modulation of CaSR inhibits ADMA driven lipid accumulation. Further investigation using CaSR overexpressing HEK293 cells demonstrated that ADMA potentiates CaSR signalling via Gq intracellular Ca2+ mobilisation. This study identifies a signalling mechanism for ADMA as an endogenous ligand of the G protein-coupled receptor CaSR that potentially contributes to the impact of ADMA in cardiometabolic disease.
| Item Type: | Articles |
|---|---|
| Additional Information: | This study was supported by MRC intramural funding to J.L and British Heart Foundation Centre of Research Excellence Award (RE/13/5/30177). |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Alghamdi, Fatmah and Dowsett, Dr Laura and Salt, Dr Ian and Leiper, Professor James and Higgins, Miss Erin |
| Authors: | Dowsett, L., Duluc, L., Higgins, E., Alghamdi, F., Fast, W., Salt, I. P., and Leiper, J. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health College of Medical Veterinary and Life Sciences > School of Molecular Biosciences |
| Journal Name: | Cellular Signalling |
| Publisher: | Elsevier |
| ISSN: | 0898-6568 |
| ISSN (Online): | 1873-3913 |
| Published Online: | 05 April 2023 |
| Copyright Holders: | Copyright © 2023 The Authors |
| First Published: | First published in Cellular Signalling 107: 110676 |
| Publisher Policy: | Reproduced under a Creative Commons License |
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