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Role of cannabinoid receptors in alcoholic hepatic injury: steatosis and fibrogenesis are increased in CB 2 receptor‐deficient mice and decreased in CB 1 receptor knockouts
Author(s) -
Trebicka Jonel,
Racz Ildiko,
Siegmund Sören V.,
Cara Erlind,
Granzow Michaela,
Schierwagen Robert,
Klein Sabine,
Wojtalla Alexandra,
Hennenberg Martin,
Huss Sebastian,
Fischer HansPeter,
Heller Jörg,
Zimmer Andreas,
Sauerbruch Tilman
Publication year - 2011
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/j.1478-3231.2011.02496.x
Subject(s) - steatosis , cannabinoid receptor , receptor , gene knockout , endocannabinoid system , cannabinoid , cannabinoid receptor type 2 , liver injury , knockout mouse , medicine , endocrinology , biology , gene , biochemistry , agonist
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 CB 1 and CB 2 in the hepatic response to chronic alcohol intake, we examined CB knockout mice (CB 1 −/− , CB 2 −/− ). Methods: Eight‐ to 10‐week‐old CB 1 −/− , CB 2 −/− 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 CB 1 −/− mice after ethanol intake. Ethanol intake in CB 2 −/− mice induced much higher steatosis (SREBP‐1c mediated) and inflammation (B‐cell predominant infiltrates) compared with wild‐type animals and CB 1 −/− mice. HSC activation and collagen production were increased in all groups after forced ethanol intake, being most pronounced in CB 2 −/− mice and least pronounced in CB 1 −/− mice. Discussion: The fact that CB 2 receptor knockout mice exhibited the most pronounced liver damage after ethanol challenge indicates a protective role of CB 2 receptor expression in chronic ethanol intake. By contrast, in CB 1 knockouts, the effect of ethanol was attenuated, suggesting aggravation of fibrogenesis and SREBP‐1c‐mediated steatosis via CB 1 receptor expression after ethanol intake.