Hepatocyte cholesterol content modulates glucagon receptor signalling

Area of Science:

• Biochemistry
• Cell Biology
• Pharmacology

Background:

• Cellular cholesterol levels play a role in regulating various cellular processes.
• The glucagon receptor (GCGR) is a key mediator of glucose homeostasis.
• Understanding factors that modulate GCGR activity is crucial for metabolic disease research.

Purpose of the Study:

• To investigate the impact of cellular cholesterol on glucagon receptor (GCGR) function.
• To explore the molecular mechanisms underlying cholesterol's modulation of GCGR signaling.

Main Methods:

• Assessed glucagon-mediated cAMP production, ligand internalization, and glucose production in liver cells with altered cholesterol levels.
• Utilized coarse-grained molecular dynamic simulations to study GCGR-lipid bilayer interactions.
• Measured in vivo glucagon responsiveness in mice subjected to high-cholesterol diets and simvastatin treatment.

Main Results:

• Elevated cholesterol levels decreased GCGR cAMP signaling in various cell models.
• Simvastatin treatment enhanced ex vivo glucagon-induced glucose output from mouse hepatocytes.
• High-cholesterol diet in mice led to increased hepatic cholesterol and blunted glucagon response, partially reversed by simvastatin.
• Molecular simulations suggested cholesterol binding sites on GCGR, potentially acting as a negative allosteric modulator.

Conclusions:

• Cellular cholesterol content significantly influences glucagon sensitivity.
• Identified a potential molecular basis for cholesterol's effect on GCGR.
• Findings may be relevant to understanding glucagon resistance in non-alcoholic fatty liver disease (NAFLD).