Unique pathway for anandamide synthesis and liver regeneration.

T he endocannabinoid system (ECS) includes cannabinoid (CB1 and CB2) receptors and their endogenous ligands (i.e., the endocannabinoids anandamide and 2arachydonylglycerol) as well as proteins involved in endocannabinoids biosynthesis and degradation (1). The ECS is present in the liver and undergoes adaptive changes in response to noxious stimuli. Endocannabinoids as well as CB1 and CB2 receptors (which are, respectively, either faintly or not expressed in normal livers) are up-regulated in experimental liver injury and liver cirrhosis of various etiologies. In vivo, CB1 receptor activation promotes fat accumulation, triggers inflammation in nonalcoholic and alcoholic fatty liver diseases, contributes to the progression of chronic hepatitis to cirrhosis by stimulating fibrogenesis, and is also implicated in hemodynamic and neurological consequences associated with liver cirrhosis, including portal hypertension, encephalopathy, and cardiomyopathy (2– 4). Conversely, activation of CB2 receptors exerts antifibrogenic and antiinflammatory effects in experimental models of liver disease (5). These pharmacological effects make CB2 agonists and CB1 antagonists promising candidates for the treatment of fibrosis in chronic liver pathologies. By disclosing a prominent CB1-mediated role of anandamide in the early phase of liver regeneration, Mukhopadhyay et al. (6) provide additional and significant support to the prominent role of the ECS in liver biology in an article in PNAS. The liver is unique in that it has the unlimited capacity to regenerate in response to surgical removal as well as chemical or viral insults (7). This fascinating regenerative aspect invariably recalls the ancient legend of Prometheus, the Titan who stole the secret of fire from Zeus and passed it to humans. As a punishment, Prometheus was chained to a rock, and a giant bird ate his liver every day; every night, his liver regenerated. Liver regeneration depends on the concerted action of multiple growth factors, cytokines, and hormones that induce quiescent hepatocytes and other cells (biliary ductular, Kupffer, stellate, and endothelial cells) to replicate to restore liver mass (8). Mukhopadhyay et al. (6) studied the involvement of the ECS in liver regeneration by performing a mouse surgical procedure that removes two of three liver masses, a wellestablished technique developed in the rat in 1931 (9). In contrast to other experimental models involving necrosis of lobular zones induced by toxins, partial hepatectomy is not associated with massive necrosis, and thus, regeneration of the residual lobes is mediated by processes relevant only to liver tissues and not to necrosis or acute inflammation (8). In mice, the peak proliferative response, which can be evaluated by measuring the DNA synthesis, occurs between 36 and 42 h after partial hepatectomy. From 2 d after partial hepatectomy, liver regeneration can be quantified by measurement of liver mass. Seven days after partial hepatectomy, more than 75% of the original liver mass is restored (10). The prominent role for hepatic CB1 receptor in liver regeneration was suggested by the delayed proliferative response (evaluated by quantifying the proliferating hepatocytes by bromodeoxyuridine staining at 40 h) in CB1 knockout mice, mice lacking the CB1 receptors in hepatocytes only, and WT mice treated with the CB1 antagonist rimonabant. The CB1 receptor was found to be involved in the early proliferative response only (i.e., 40 h after surgery), when the proliferative response is maximal. An increase of tissue weight was indeed observed at 40 h in WT but not CB1-deficient mice, whereas no weight differences between the two strains were observed 6 d after partial hepatectomy. These data suggests that, in the absence of CB1 receptor, hepatic regeneration was only delayed and not fully prevented. This is not surprising, because liver regeneration after partial hepatectomy is a very complex and well-orchestrated phenomenon, associated with signaling cascades involving a redundancy of hepatic mitogens (7). The transient—and not permanent— effect of CB1 activation on liver regeneration should be emphasized in the light of the possible use of CB1 antagonists in liver diseases. Indeed, the benefits of CB1 antagonists in slowing the progression O