title: A contradictory role of A1 adenosine receptor in carbon tetrachloride- and bile duct ligation-induced liver fibrosis in mice.
abstract: Mice lacking A(1) adenosine receptors (A(1)AR) were thought to be protected from developing fatty liver; however, the contribution of A(1)AR to hepatic fibrosis has not been explored. Here we found that the expression of A(1)AR was decreased in fibrotic liver induced by chronic carbon tetrachloride (CCl(4)) but increased in that induced by bile duct ligation (BDL). Therefore, we examined whether A(1)AR contributes to hepatic fibrosis in CCl(4) and BDL animal models using A(1)AR knockout mice. Compared with wild-type (WT) mice, hepatic fibrosis resulting from chronic CCl(4) exposure was attenuated in A(1)AR(-/-) mice with markedly decreased collagen deposition and reduced hepatic stellate cell activation, whereas bile duct-ligated A(1)AR(-/-) mice displayed a significant increase in hepatic fibrosis. Hepatocyte damage was reduced in A(1)AR(-/-) mice after a single injection of CCl(4), with down-regulation of CYP2E1 and UCP2 gene expression in livers, which resulted in impaired liver sensitivity to CCl(4). However, BDL caused severe bile infarcts in livers of A(1)AR(-/-) mice, with significantly elevated levels of bile acid compared with those in WT mice. CCl(4) and BDL resulted in different expression patterns of genes involved in fibrogenesis in A(1)AR(-/-) mice. These results indicate that A(1)AR 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.
authors.affiliation: Center for Molecular Metabolism, Nanjing University of Science and Technology, 200 Xiaolingwei St., Nanjing 210094, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Yang
authors.forename: Zheyi
authors.initials: Z
authors.lastname: Han
authors.forename: Peng
authors.initials: P
authors.lastname: Chen
authors.forename: Lin
authors.initials: L
authors.lastname: Zhu
authors.forename: Shiming
authors.initials: S
authors.lastname: Wang
authors.forename: Zichun
authors.initials: Z
authors.lastname: Hua
authors.forename: Jianfa
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000097:blood; D001652:Bile Ducts / Q000473:pathology; D002252:Carbon Tetrachloride Poisoning / Q000150:complications; D002908:Chronic Disease; D003094:Collagen / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis; D016207:Cytokines / Q000378:metabolism; D015536:Down-Regulation; D007473:Ion Channels / Q000096:biosynthesis; D008026:Ligation; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D045726:Metalloproteases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000096:biosynthesis; D043682:Receptor, Adenosine A1 / Q000235:genetics / Q000502:physiology*; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D000071246:Uncoupling Protein 2
chemical_list: D001647:Bile Acids and Salts; D016207:Cytokines; D007473:Ion Channels; D024101:Mitochondrial Proteins; D043682:Receptor, Adenosine A1; D019714:Tissue Inhibitor of Metalloproteinases; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; D003094:Collagen; D019392:Cytochrome P-450 CYP2E1; D045726:Metalloproteases