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Glucose Sensor That Controls Glucose Metabolism Identified

by VR Sreeraman on  December 27, 2006 at 4:53 PM Research News   - G J E 4
Glucose Sensor That Controls Glucose Metabolism Identified
Scientists from Scripps Research Institute, have identified a sensor that identifies glucose levels. This sensor plays an important role in metabolism of glucose. It acts like a switch that increases or decreases the manufacture of glucose inside the human liver. At other times it helps to convert glucose into fat for the purpose of storage in adipose tissue. This sensor is named Liver X Receptor. Its dual function makes it a potential site that can be targeted to treat clinical disorders such as diabetes and obesity. This research may also be the forerunner for therapies for stroke and other heart diseases.
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In some recent animal studies, Saez pointed out, activation of LXRs using synthetic molecules also induced regression of atherosclerosis, the clogging, narrowing, and hardening of the body's large arteries and blood vessels that can lead to stroke, heart attack, and eye and kidney problems. Elevated levels of pathogenic cholesterols, also known to bind LXR, are a primary risk for development of atherosclerosis.

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"The integration of glucose sensing and control of lipogenesis by LXR may explain why low-fat/high-carbohydrate diets induce hypertriglyceridemia [an elevated level of triglycerides in the blood]," Saez said. "LXR can sense surplus glucose, induce fatty acid synthesis, and prompt the liver's export of triglycerides into the bloodstream. Since LXR acts as the body's sensor of a buildup of pathogenic cholesterol, its ability to bind both glucose and oxysterols suggests that LXR may be a link between hyperglycemia and atherosclerosis."

In fact, Saez and his colleagues originally looked at LXR as a drug target for atherosclerosis. But when they fed synthetic LXR ligands to mice to induce activation, they discovered that the mice metabolized glucose more effectively and that activation suppressed new production of glucose in the liver.

That prompted the scientists to look more closely at glucose levels as the LXR activating mechanism in the liver.

To their surprise, what Saez and his colleagues discovered was that glucose bound directly to LXR. This was unexpected because the carbohydrate does not conform to the standard definition of a typical ligand that activates nuclear receptors, transcription factors that coordinate gene expression in response to hormonal and environmental signals. This discovery, Saez said, represents the first signaling pathway where a carbohydrate activates a nuclear receptor, although the precise mode of binding remains unknown.

As part of the study, mice were put on exclusive sucrose or D-glucose diets; all diets were devoid of cholesterol to minimize naturally occurring oxysterols. D-glucose and GW3965 (a synthetic LXR activator) induced similar changes in hepatic gene expression, indicating that LXR functions as a glucose sensor in vivo that responds to increasing liver glucose uptake. The ability of the LXRs to respond to glucose and its derivatives was very specific: no effect was seen in other nuclear receptors tested.

The current study focused primarily on the role of glucose sensing in the liver and gut. New studies will focus on the question of whether glucose levels in other tissue types, such as the pancreas, activate LXR, Saez added.

Source: Eurekalert
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