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Hepatocyte cholesterol content modulates glucagon receptor signalling
- Source :
- Molecular Metabolism, Vol 63, Iss , Pp 101530- (2022)
- Publication Year :
- 2022
- Publisher :
- Elsevier, 2022.
-
Abstract
- Structured abstract: Objective: To determine whether glucagon receptor (GCGR) actions are modulated by cellular cholesterol levels. Methods: We determined the effects of experimental cholesterol depletion and loading on glucagon-mediated cAMP production, ligand internalisation and glucose production in human hepatoma cells, mouse and human hepatocytes. GCGR interactions with lipid bilayers were explored using coarse-grained molecular dynamic simulations. Glucagon responsiveness was measured in mice fed a high cholesterol diet with or without simvastatin to modulate hepatocyte cholesterol content. Results: GCGR cAMP signalling was reduced by higher cholesterol levels across different cellular models. Ex vivo glucagon-induced glucose output from mouse hepatocytes was enhanced by simvastatin treatment. Mice fed a high cholesterol diet had increased hepatic cholesterol and a blunted hyperglycaemic response to glucagon, both of which were partially reversed by simvastatin. Simulations identified likely membrane-exposed cholesterol binding sites on the GCGR, including a site where cholesterol is a putative negative allosteric modulator. Conclusions: Our results indicate that cellular cholesterol content influences glucagon sensitivity and indicate a potential molecular basis for this phenomenon. This could be relevant to the pathogenesis of non-alcoholic fatty liver disease, which is associated with both hepatic cholesterol accumulation and glucagon resistance.
Details
- Language :
- English
- ISSN :
- 22128778
- Volume :
- 63
- Issue :
- 101530-
- Database :
- Directory of Open Access Journals
- Journal :
- Molecular Metabolism
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.30118452e1cf4e4dad65c30c5ab019ba
- Document Type :
- article
- Full Text :
- https://doi.org/10.1016/j.molmet.2022.101530