SREBP-1c and its downstream target FASN, but in genotype 1 patients there was no correlation. Clinical studies in CHC have hinted at the importance of CB1 stimulation to steatosis, with daily cannabis use a risk factor for steatosis severity in over 300 patients with CHC. In experimental work, endocannabinoid stimulation of CB1 mediates diet-induced steatosis, since CB1 knockout mice fed a high fat diet are resistant to steatosis. Likewise, treatment of wild type mice with a CB1 agonist induces de novo fatty acid synthesis via increased hepatic expression of SREBP-1c and its downstream targets FASN and acetyl coenzyme-A carboxylase-1. Finally, the selective deletion of hepatocyte CB1 receptors alone is sufficient to prevent diet and alcohol-induced hepatic steatosis. The endocannabinoid system plays an important role in liver fibrosis. In three murine models of chronic liver injury, CB1 receptor antagonism by pharmacological or genetic means reduced fibrosis area, TGF-b1 expression and the accumulation of fibrogenic cells. It has also been shown that CB1 can mediate liver fibrosis through effects on apoptosis and the growth of hepatic myofibroblasts. Clinical studies first Nilotinib demonstrated the likely importance of this system in patients with CHC, showing daily cannabis smoking to be independently associated with the progression and severity of fibrosis. In our study, CB1 was expressed in all patients with CHC and increased with advancing fibrosis, with the highest levels present in those with cirrhosis. We were unable to show any relationship between CB1 receptor expression and inflammatory grade, although this does not exclude that the endocannabinoid system via CB1 may mediate fibrosis in this way. Rather, it has been suggested that HCV can directly activate and stimulate hepatic stellate cells through its core and non-structural proteins, or via secretions from infected hepatocytes. In this context, activated HSCs not only secrete collagens and cytokines, but also the endocannabinoid 2-AG, which in turn up-regulates and activates hepatocyte CB1. Stimulation of hepatocyte CB1 through this pathway or directly by HCV as we demonstrate will serve to amplify the pathways by which liver fibrosis develops in CHC. It is interesting to note from our immunohistochemistry that CB1 receptors were up-regulated on hepatic stellate cells in CHC. One could therefore speculate that the direct pro-fibrogenic interactions between HCV and stellate cells demonstrated by Battaler and collegues may in part, be mediated through and exaggerated by the induction of CB1. There has been much recent interest in the use of CB1 antagonists to treat both hepatic and metabolic disease and our findings emphasize the likely usefulness of these compounds in patients with hepatitis C. In addition to the amelioration of steatosis and fibrosis, CB1 blockade reduces portal pressure and can reverse mesenteric arterial dilation, making them useful in end stage liver disease as well. We speculate that CB1 antagonism may also have an inhibitory effect on HCV replication.