Hepatitis C Virus Induces the Cannabinoid Receptor 1

Abstract

BackgroundActivation 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.MethodsCB1 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 FindingsCB1 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/SignificanceCB1 is up-regulated in CHC and is associated with increased steatosis in genotype 3. It is induced by the hepatitis C virus.

Insulin resistance and chronic liver disease

“…In patients with HCV genotype 3, hepatic steatosis directly correlates with circulating and hepatic viral load, which is mediated by an impaired verylow-density lipoprotein assembly and secretion and by an up-regulation of the sterol depending protein signaling pathway, which regulates de novo lipogenesis and inhibits mitochondrial fatty acid b-oxidation [63,64] .…”

Organelle dysfunction in hepatitis C virus-associated steatosis: anything to learn from nonalcoholic steatohepatitis?

“…We recently demonstrated that the cannabinoid receptor CB1 is upregulated in patients with CHC and in HCV-infected hepatic cells in vitro [93], suggesting a novel mechanism for HCV-induced steatosis. Endocannabinoids binding to the CB1 receptor are prolipogenic, upregulating SREBP-1c, ACC-1 and FAS to increase de novo FA synthesis [94].…”

Marijuana Use Is Not Associated With Progression to Advanced Liver Fibrosis in HIV/Hepatitis C Virus–coinfected Women

“…CB1 is upregulated in chronic liver disease including HCV infection [12]. CB2 is also upregulated in chronic liver disease and prevents fibrosis progression [3,32,33], possibly through inhibition of hepatic myofibroblasts, or by increasing hepatocyte survival [11], downregulation of interleukin 17 [34], and modulation of Kupffer cells [35].…”