Cannabinoid receptor 1 signaling in hepatocytes and stellate cells does not contribute to NAFLD

The endocannabinoid system regulates appetite and energy expenditure and inhibitors of cannabinoid receptor 1 (CB-1) induce weight loss with improvement in components of the metabolic syndrome. While CB-1 blockage in brain is responsible for weight loss, many of the metabolic benefits associated with CB-1 blockade have been attributed to inhibition of CB-1 signaling in the periphery. As a result, there has been interest in developing a peripherally restricted CB-1 inhibitor for the treatment of nonalcoholic fatty liver disease (NAFLD) that would lack the unwanted centrally mediated side effects. Here, we produced mice that lacked CB-1 in hepatocytes or stellate cells to determine if CB-1 signaling contributes to the development of NAFLD or liver fibrosis. Deletion of CB-1 in hepatocytes did not alter the development of NAFLD in mice fed a high-sucrose diet (HSD) or a high-fat diet (HFD). Similarly, deletion of CB-1 specifically in stellate cells also did not prevent the development of NAFLD in mice fed the HFD, nor did it protect mice from carbon tetrachloride-induced fibrosis. Combined, these studies do not support a direct role for hepatocyte or stellate cell CB-1 signaling in the development of NAFLD or liver fibrosis.