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Hepatic glucose sensing: does flux matter?

Masakazu Shiota¹, Mark A Magnuson

¹Department of Molecular Physiology and Biophysics and Vanderbilt Center for Stem Cell Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.

The Journal of Clinical Investigation

|February 23, 2008

Summary

Liver X receptors (LXRs) do not sense glucose independently. Instead, carbohydrate-responsive element-binding protein (ChREBP) is key for regulating lipogenic genes in response to carbohydrates.

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Area of Science:

Metabolic regulation
Hepatology
Molecular endocrinology

Background:

Liver X receptors (LXRs) are nuclear receptors involved in lipid metabolism.
The role of LXRs in direct glucose sensing by the liver remains debated.
Previous studies suggested LXRalpha/beta might sense glucose independent of metabolic flux.

Purpose of the Study:

To investigate the role of liver X receptors (LXRs) LXRalpha and LXRbeta in hepatic carbohydrate sensing.
To clarify the mechanism by which the liver senses and responds to carbohydrates.
To reconcile conflicting findings regarding LXR function in glucose metabolism.

Main Methods:

Utilized LXRalpha/beta double-knockout (KO) mice to study liver function.
Compared findings with a recent report in Nature.
Analyzed the regulation of lipogenic genes.

Main Results:

Results strongly contradict the notion that LXRalpha/beta sense glucose independent of metabolic flux.
Demonstrated that LXRalpha/beta are not the primary sensors of glucose in the liver.
Findings support a critical role for carbohydrate-responsive element-binding protein (ChREBP) in mediating glucose and carbohydrate effects on lipogenic genes.

Conclusions:

Liver X receptors (LXRs) do not directly sense glucose in the liver.
Carbohydrate-responsive element-binding protein (ChREBP) plays a central role in mediating the effects of carbohydrates on lipogenesis.
This study clarifies the molecular players involved in hepatic carbohydrate sensing and lipogenic gene regulation.