Hepatitis C Virus Induces the Cannabinoid Receptor 1

Abstract

Background: Activation of hepatic CB1 receptors (CB1) is associated with steatosis and fibrosis in experimental forms of liver disease. However, CB1 expression has not been assessed in patients with chronic hepatitis C (CHC), a disease associated with insulin resistance, steatosis and metabolic disturbance. We aimed to determine the importance and explore the associations of CB1 expression in CHC. Methods: CB1 receptor mRNA was measured by real time quantitative PCR on extracted liver tissue from 88 patients with CHC (genotypes 1 and 3), 12 controls and 10 patients with chronic hepatitis B (CHB). The Huh7/JFH1 Hepatitis C virus (HCV) cell culture model was used to validate results. Principal Findings: CB1 was expressed in all patients with CHC and levels were 6-fold higher than in controls (P,0.001). CB1 expression increased with fibrosis stage, with cirrhotics having up to a 2 fold up-regulation compared to those with low fibrosis stage (p,0.05). Even in mild CHC with no steatosis (F0-1), CB1 levels remained substantially greater than in controls (p,0.001) and in those with mild CHB (F0-1; p,0.001). Huh7 cells infected with JFH-1 HCV showed an 8-fold upregulation of CB1, and CB1 expression directly correlated with the percentage of cells infected over time, suggesting that CB1 is an HCV inducible gene. While HCV structural proteins appear essential for CB1 induction, there was no core genotype specific difference in CB1 expression. CB1 significantly increased with steatosis grade, primarily driven by patients with genotype 3 CHC. In genotype 3 patients, CB1 correlated with SREBP-1c and its downstream target FASN (SREBP-1c; R = 0.37, FASN; R = 0.39, p,0.05 for both). Conclusions/Significance: CB1 is up-regulated in CHC and is associated with increased steatosis in genotype 3. It is induced by the hepatitis C virus. C