The nuclear receptor LXR is a glucose sensor

Area of Science:

• Metabolic regulation
• Molecular biology
• Hepatology

Background:

• The liver plays a crucial role in maintaining glucose homeostasis through production and consumption.
• Insulin and ChREBP are known regulators of hepatic glucose metabolism and lipogenesis.
• The precise mechanisms by which glucose influences its own metabolic fate are still under investigation.

Purpose of the Study:

• To investigate a novel mechanism by which glucose regulates its own metabolic fate in the liver.
• To determine if glucose directly interacts with and modulates the activity of the liver X receptor (LXR).

Main Methods:

• Biochemical assays to test direct binding and activation of LXR-alpha and LXR-beta by glucose and glucose-6-phosphate.
• Gene expression analysis of LXR target genes in response to glucose.
• In vivo studies in mice to assess the impact of a glucose diet on cholesterol homeostasis genes.

Main Results:

• d-Glucose and d-glucose-6-phosphate were identified as direct agonists of both LXR-alpha and LXR-beta.
• Glucose activates LXR at physiological liver concentrations, inducing target gene expression similarly to oxysterols.
• Expression of LXR-dependent cholesterol homeostasis genes was upregulated in mice refed with glucose, confirming glucose as an endogenous LXR ligand.

Conclusions:

• The liver X receptor (LXR) acts as a transcriptional switch integrating hepatic glucose metabolism and fatty acid synthesis.
• Glucose directly stimulates LXR, providing a new molecular link between glucose availability and lipid metabolism.
• This study uncovers a previously unrecognized pathway for glucose regulation of hepatic lipid synthesis.