title: Hepatitis C virus induces the cannabinoid receptor 1.
abstract: BACKGROUND
  Activation of hepatic CB(1) receptors (CB(1)) is associated with steatosis and fibrosis in experimental forms of liver disease. However, CB(1) 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 CB(1) expression in CHC.
  
  
  METHODS
  CB(1) 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.
  
  
  RESULTS
  CB(1) was expressed in all patients with CHC and levels were 6-fold higher than in controls (P<0.001). CB(1) 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), CB(1) 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 CB(1), and CB(1) expression directly correlated with the percentage of cells infected over time, suggesting that CB(1) is an HCV inducible gene. While HCV structural proteins appear essential for CB(1) induction, there was no core genotype specific difference in CB(1) expression. CB(1) significantly increased with steatosis grade, primarily driven by patients with genotype 3 CHC. In genotype 3 patients, CB(1) correlated with SREBP-1c and its downstream target FASN (SREBP-1c; R=0.37, FASN; R=0.39, p<0.05 for both).
  
  
  CONCLUSIONS
  CB(1) is up-regulated in CHC and is associated with increased steatosis in genotype 3. It is induced by the hepatitis C virus.
authors.affiliation: Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Sydney, Australia.
authors.forename: David
authors.initials: D
authors.lastname: van der Poorten
authors.forename: Mahsa
authors.initials: M
authors.lastname: Shahidi
authors.forename: Enoch
authors.initials: E
authors.lastname: Tay
authors.forename: Jayshree
authors.initials: J
authors.lastname: Sesha
authors.forename: Kayla
authors.initials: K
authors.lastname: Tran
authors.forename: Duncan
authors.initials: D
authors.lastname: McLeod
authors.forename: Jane S
authors.initials: JS
authors.lastname: Milliken
authors.forename: Vikki
authors.initials: V
authors.lastname: Ho
authors.forename: Lionel W
authors.initials: LW
authors.lastname: Hebbard
authors.forename: Mark W
authors.initials: MW
authors.lastname: Douglas
authors.forename: Jacob
authors.initials: J
authors.lastname: George
mesh_terms: D000328:Adult; D002460:Cell Line; D005260:Female; D016174:Hepacivirus / Q000235:genetics / Q000502:physiology*; D019698:Hepatitis C, Chronic / Q000235:genetics* / Q000378:metabolism / Q000821:virology; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000821:virology; D008297:Male; D008875:Middle Aged; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D043884:Receptor, Cannabinoid, CB1