Imperial College London
Alternate

ProfessorDavidCarling

Faculty of Medicine, Institute of Clinical Sciences

Professor of Biochemistry
 
 
 
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Contact

 

+44 (0)7590 250 559david.carling

 
 
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Location

 

2.14DLMS BuildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{McGlone:2022:10.1016/j.molmet.2022.101530,
author = {McGlone, ER and Dunsterville, C and Carling, D and tomas, A and Bloom, S and Tan, T and Jones, B},
doi = {10.1016/j.molmet.2022.101530},
journal = {Molecular Metabolism},
title = {Hepatocyte cholesterol content modulates glucagon receptor signalling},
url = {http://dx.doi.org/10.1016/j.molmet.2022.101530},
volume = {63},
year = {2022}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - ObjectiveTo determine whether glucagon receptor (GCGR) actions are modulated by cellular cholesterol levels.MethodsWe 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.ResultsGCGR 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.ConclusionsOur 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.
AU  - McGlone,ER
AU  - Dunsterville,C
AU  - Carling,D
AU  - tomas,A
AU  - Bloom,S
AU  - Tan,T
AU  - Jones,B
DO  - 10.1016/j.molmet.2022.101530
PY  - 2022///
SN  - 2212-8778
TI  - Hepatocyte cholesterol content modulates glucagon receptor signalling
T2  - Molecular Metabolism
UR  - http://dx.doi.org/10.1016/j.molmet.2022.101530
UR  - https://www.sciencedirect.com/science/article/pii/S2212877822000990
UR  - http://hdl.handle.net/10044/1/97808
VL  - 63
ER  -
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