A Contradictory Role of A1 Adenosine Receptor in Carbon Tetrachloride- and Bile Duct Ligation-Induced Liver Fibrosis in Mice

Mice lacking A₁ adenosine receptors (A₁AR) were thought to be protected from developing fatty liver; however, the contribution of A₁AR to hepatic fibrosis has not been explored. Here we found that the expression of A₁AR was decreased in fibrotic liver induced by chronic carbon tetrachloride (CCl₄) but increased in that induced by bile duct ligation (BDL). Therefore, we examined whether A₁AR contributes to hepatic fibrosis in CCl₄ and BDL animal models using A₁AR knockout mice. Compared with wild-type (WT) mice, hepatic fibrosis resulting from chronic CCl₄ exposure was attenuated in A₁AR(−/−) mice with markedly decreased collagen deposition and reduced hepatic stellate cell activation, whereas bile duct-ligated A₁AR(−/−) mice displayed a significant increase in hepatic fibrosis. Hepatocyte damage was reduced in A₁AR(−/−) mice after a single injection of CCl₄, with down-regulation of CYP2E1 and UCP2 gene expression in livers, which resulted in impaired liver sensitivity to CCl₄. However, BDL caused severe bile infarcts in livers of A₁AR(−/−) mice, with significantly elevated levels of bile acid compared with those in WT mice. CCl₄ and BDL resulted in different expression patterns of genes involved in fibrogenesis in A₁AR(−/−) mice. These results indicate that A₁AR participates in the pathogenesis of hepatic fibrosis with a complex mechanism, and the effect of targeting adenosine and its receptors in the prevention of hepatic fibrosis should be cautiously evaluated.