The best known endocannabinoid receptors are in the brain, and responsible for the psychoactive effects of marijuana.

But in the March 2008 issue of Cell Metabolism, researchers from the National Institute on Alcohol Abuse and Alcoholism report that endocannabinoid receptors also stimulate the main type of liver cells, the hepatocytes, to store excess fat. Such storage can lead to alcoholic fatty liver or steatosis, a disease in itself and the possible precursor to even more serious liver conditions such as cirrhosis.

Furthermore, the endocannabinoids that activate them are secreted by another liver cell type: the hepatic stellate cell, a support cell known to date for its role in structural support and secreting collagen, which is important in injury repair but also can lead to fibrosis.

The new findings "bring the hepatic stellate cell into the picture," senior author George Kunos, senior investigator at the National Institute on Alcohol Abuse and Alcoholism, told BioWorld Today. "So far, it had not been implicated in the development of fatty liver."

As receptor families go, the endocannabinoid one is small - as of now it consists of just two members: CB1 and CB2. CB1 receptors are found in the nervous system and in the liver, while CB2 receptors are associated mainly with inflammatory and immune cells.

The researchers were spurred to investigate whether endocannabinoids are involved in fatty liver disease because alcoholic fatty liver has similarities to fatty liver induced by a high-fat diet, where endocannabinoids play a role. When Kunos and his team fed animals a diet consisting mainly of alcohol, they found that hepatic stellate cells developed elevated levels of 2-arachidonoylglycerol or 2-AG, one of the two ligands for CB1 receptors.

When the hepatic stellate cells secrete that 2-AG, it stimulates the CB-1 receptors on hepatocytes in the vicinity. "The actual accumulation of fat occurs on the hepatocyte," Kunos said, and leads to liver damage.

The specificity of alcohol's effect on both 2-AG and hepatic stellate cells, Kunos noted, were surprising, since "there is no known specific receptor target for alcohol." The researchers showed that neither alcohol nor its metabolites had an effect on isolated hepatic stellate cells, and alcohol metabolites did not lead to the development of fatty liver. Together, Kunos said, the results suggested that the effect of alcohol on stellate cells in vivo is an indirect one, possibly mediated by bacterial endotoxin - though he noted that the endotoxin connection is "speculative" at this point.

To make sure that the effects they were seeing were due to endocannabinoid action directly on liver cells, rather than in the brain, the researchers generated a knockout mouse that lacked CB-1 receptors specifically in the liver. Such mice did not develop fatty liver disease on a high-alcohol diet.

"The brain can influence liver metabolism through the autonomic nervous system," Kunos explained. The appetite regulator leptin, for example, influences the way the liver metabolizes carbohydrates - but leptin's site of action is in the brain. "It may still be that the central nervous system contributes" to the altered fat metabolism that leads to fatty liver, Kunos said. But the effect of deleting CB-1 receptors on the hepatocytes shows that liver receptors play an important role in the effect.

The researchers then treated another group of mice with the endocannabinoid blocker Acomplia (rimonabant, Sanofi-Aventis Group) and found that those mice, too, were protected from fatty liver disease due to excess alcohol. "The present findings suggest that treatment with a CB1 antagonist may slow the development of fatty liver and thus prevent or delay its progression to more severe and irreversible forms of liver disease."

Kunos also noted that the findings might give a shot in the arm to the U.S. prospects of endocannabinoid antagonists for the treatment of obesity-related fatty liver. Rimonabant, the drug used in the Cell Metabolism study, is approved in the European Union, but has yet to gain FDA clearance, partly because of concern with side effects that are due to the drug's action on brain receptors. But if new types of antagonists are developed that do not cross the blood-brain barrier, they might have promise for the treatment of fatty liver regardless of its origin.