Clinical

Endogenous cannabinoid may protect liver from fibrosis

Last Updated: 2004-05-17 16:15:01 -0400 (Reuters Health)

By Karla Gale

NEW ORLEANS (Reuters Health) - The endogenous cannabinoid anandamide seems to protect the liver from fibrosis by inducing necrotic cell death in hepatic stellate cells but not in hepatocytes, according to a presentation here Sunday at Digestive Disease Week.

Serum levels of anandamide (arachidonoyl ehanolamide), a lipid signaling molecule synthesized and released by endothelial cells, macrophages and platelets, are high in patients with liver disease, presenter Dr. Soeren V. Siegund told attendees. "Anadamide rapidly and dose dependently induces dell death in human and rat stellate cells," Dr. Siegund said.

In the study, microscopic morphology and staining patterns indicated that the mechanism of death was necrosis rather than apoptosis. Sublethal doses of anadamide inhibited stellate cell proliferation, even when cells were exposed to a strong inducer of cell proliferation.

Anandamide treatment increased formation of reactive oxygen species. It is apparent that the compound interacts with membrane cholesterol, noted the researcher, from Columbia University in New York, since depletion of cholesterol from cell membranes prevented reactive oxygen species formation and delayed anandamide -induced cell death.

However, it is not simply a matter of disrupting cell membrane, he added. "We did an experiment where we pretreated cells with MCD [a compound that depletes membrane cholesterol] and washed the cells and placed them in fresh medium. Still, cell death was increased when anandamide was added to the medium."

In an interview with Reuters Health, Dr. Siegmund noted that serum levels of anandemide are high in patients with viral or alcoholic hepatitis and in those with cirrhosis.

"It could be that anandamide metabolism is slower because of damage to hepatocytes, or it could be induced by activated immune cells," he suggested.

Normally, anandamide is metabolized very rapidly. Future studies will look at the effect of methanandamide, a more stable compound, and that of exogenous cannabinoids, such as THC, the active compound in marijuana. They also hope to examine the effects of these agents in vivo, in healthy animals and in those with liver disease.

But at this point, it is too soon to say that it actually inhibits fibrosis in vivo, he added.

Digestive Disease Week is the annual meeting of the American Gastroenterological Association, the American Association for the Study of Liver Diseases, the Gastroenterology Research Group, the Society for Surgery of the Alimentary Tract, and the American Society for Gastrointestinal Endoscopy.