LXR binds to both glucose and pathogenic cholesterol, regulates fat synthesis and triglyceride levels.

La Jolla, Ca – TSRI – In a new study, scientists at The Scripps Research Institute have described for the first time a glucose activated sensor that acts as a switch to decrease production of endogenous glucose in the liver, and increase conversion of glucose to fat for storage in adipose tissue. This dual action makes the sensor, Liver X Receptor, a potential target for new therapies aimed at obesity and diabetes. The research may also have implications for heart disease and stroke.

The study was published December 20 in an advanced, online edition of the journal Nature, and was supported by the Genomics Institute of the Novartis Research Foundation.

In the study, glucose is shown to stimulate the activity of the Liver X Receptors (LXR) a and b. The LXRs act as sensors of dietary components, orchestrating the body’s response to nutrients such as oxysterols (short-lived derivatives of cholesterol) and controlling gene expression linked to cholesterol and fat metabolism.

“When you eat, glucose pours into the gut and is recognized by LXR in the liver, which then activates expression of the enzymes that turn excess glucose into triglycerides that are stored as fat,” said Enrique Saez, a Scripps Research scientist who led the study. “The fact that our study demonstrates that LXR does both—it binds to glucose and it induces fatty acid synthesis—is significant and makes LXR a potential target for diabetes and obesity treatments.”

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.

“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.

Editorial note:  It is a bit difficult to grasp the whole metabolic picture here, and more research will help clarify all the interactions taking place in the human liver, which is the master processor of our bodies’ metabolic biochemistry. However, this dual role of the Liver X Receptor might help explain the seemingly paradoxical finding that a low fat, high carb diet can often increase the amount of fat (triglycerides) in the blood, while eating (healthy, non-trans) fat can often improve the lipid and cholesterol profile. If cholesterol derivatives (which can temporarily increase after we eat certain fatty foods) act like the synthetic LXR ligands and actually improve glucose metabolism, then eating a moderate (healthy) fat, lower carb (and slower carb) diet might move us farther away from high blood sugar, obesity, and the metabolic syndrome – Dr. Z.