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Unchartered Territory
PNAS Publication Provides First Time Evidence that Activation of the EC System Directly Impacts Metabolism

"We dis-covered an entirely new mechanism which could represent a wide-spread regulatory pathway and presents a new way of potentially manipulating metabolism with targeted pharmacology.”

In a collaboration that CHORI senior scientist Ronald Krauss, MD, hopes will provide a model for continued interdisciplinary research, Dr. Krauss, a graduate student in his lab, Maxwell A. Ruby, and their colleagues at the University of California, Berkeley’s Environmental Chemistry and Toxicology Laboratory have just published a study in the latest issue of the Proceedings of the National Academy of Sciences (PNAS) that demonstrates the impact of endocannibinoid (EC) activation on blood cholesterol and triglyceride metabolism.

“This is the first time it’s been demonstrated that increases in these lipids are directly due to activation of the EC system,” Dr. Krauss explains.

The EC system is a pathway just discovered within the last 10 years that involves the regulation of many of the systems that cause obesity and metabolic disorders.

As Dr. Krauss explains, “One of the common effects of activating this system is increased food intake, and that has been major focus of the work in this area because it’s well known that the major cause of obesity is overeating.”

While the EC system is the same pathway that is activated by cannabinoids, otherwise known as marijuana, until recently it wasn’t known that the body has its own natural substances that active the EC system.

Previous studies illustrated that activation of the EC system could be prevented with a receptor blocker, rimonabant. In addition to promoting weight loss, the drug resulted in significant improvements in overall metabolic health, such as lowering triglycerides (TGs) and “bad cholesterol,” or LDL, and increasing good cholesterol, or HDL. No studies, however, had clearly identified whether those improvements were due to the decrease in food intake and/or weight loss, or to the direct metabolic effects of suppressing the EC system.

Until now. Thanks to the collaboration with UCB formed through Mr. Ruby and another former graduate student, Daniel K. Nomura, PhD, Dr. Krauss was able to utilize a new drug first identified by Dr. Nomura and his advisor, UCB’s John Casida, PhD, that allowed the EC system to be studied in a more active form than has ever been previously achieved.
“Using this novel com-pound we were able to study the full effects of the active EC system over the short term, in a period of hours, in which there was no change in food intake or body weight that could other-wise impact TG levels.”
“Sure enough," says Dr. Krauss, "we discovered that increasing the levels of EC increased TG levels by threefold.”

This is particularly important in that it provides evidence that targeting the EC pathway by EC receptor blockers such as rimonabant can improve blood lipid profiles beyond the benefit that would be expected from weight loss. However, to date, such blockers have not yet been approved in the U.S. because of effects in the brain that can lead to psychiatric disturbances in some individuals.

“It’s possible that a drug could be developed that would have a selective effect and not impact the brain, and our studies predict that such drugs would be beneficial,” says Dr. Krauss.

However, the PNAS study more importantly identifies a whole new territory for exploration that could eventually provide the key to improving risk for heart disease.
The new mechanism described in the PNAS publication suggests that EC activation alters apolipoprotein E (apoE), a protein component of blood lipoproteins. Under normal conditions, apo E is involved in clearing TGs from blood, but EC activation interferes with this apo E function.

“This new mechanism we’ve discovered is a novel target all by itself, and if we can work on understanding that mechanism better, we wouldn’t have to rely on trying to develop a blocking agent that doesn’t also impact the brain,” Dr. Krauss explains.

This is in fact that is exactly what Dr. Krauss, Mr. Ruby and their colleagues intend to do. With a provisional patent already in-hand, they are seeking to elucidate the impact of the apo E alteration on metabolism of HDL as well as TGs, and to further explore the novel mechanism as a potential new drug target.

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Tuesday, May 17, 2011 8:19 AM

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