Background: Alcohol is a common cause of hepatic liver injury with steatosis and fibrosis. Cannabinoid receptors (CB) modulate steatosis, inflammation and fibrogenesis. To investigate the differences between CB₁ and CB₂ in the hepatic response to chronic alcohol intake, we examined CB knockout mice (CB₁^−/−, CB₂^−/−).

Methods: Eight‐ to 10‐week‐old CB₁^−/−, CB₂^−/− and wild‐type mice received 16% ethanol for 35 weeks. Animals receiving water served as controls. We analysed triglyceride and hydroxyproline contents in liver homogenates. mRNA levels of CBs, pro‐inflammatory cytokines [tumour necrosis factor (TNF)‐α, monocyte chemotactic protein (MCP)‐1, interleukin (IL)‐1β] and profibrotic factors [α‐smooth muscle actin (α‐SMA), procollagen‐Ia, platelet‐derived growth factor β receptor (PDGFβ‐R)] were analysed by reverse transcription‐polymerase chain reaction (RT‐PCR). Histology (hemalaun and eosin, oil‐red O, CD3, CD45R, CD45, F4/80, Sirius red) characterized hepatic steatosis, inflammation and fibrosis. Activation of lipogenic pathways, activation and proliferation of hepatic stellate cell (HSC) were assessed by western blot [fatty acid synthase (FAS), sterol regulatory element binding protein 1c (SREBP‐1c), α‐SMA, proliferating cell nuclear antigen (PCNA), cathepsin D].

Results: Hepatic mRNA levels of the respective CBs were increased in wild‐type animals and in CB₁^−/− mice after ethanol intake. Ethanol intake in CB₂^−/− mice induced much higher steatosis (SREBP‐1c mediated) and inflammation (B‐cell predominant infiltrates) compared with wild‐type animals and CB₁^−/− mice. HSC activation and collagen production were increased in all groups after forced ethanol intake, being most pronounced in CB₂^−/− mice and least pronounced in CB₁^−/− mice.

Discussion: The fact that CB₂ receptor knockout mice exhibited the most pronounced liver damage after ethanol challenge indicates a protective role of CB₂ receptor expression in chronic ethanol intake. By contrast, in CB₁ knockouts, the effect of ethanol was attenuated, suggesting aggravation of fibrogenesis and SREBP‐1c‐mediated steatosis via CB₁ receptor expression after ethanol intake.