Galectin-3 regulates myofibroblast activation and hepatic fibrosis.
Central to fibrogenesis and the scarring of organs is the activation of fibroblasts into matrix-secreting myofibroblasts. We demonstrate that Galectin-3 expression is up-regulated in established human fibrotic liver disease and is temporally and spatially related to the induction and resolution of experimental hepatic fibrosis. Disruption of the Galectin-3 gene blocks myofibroblast activation and procollagen (I) expression in vitro and in vivo, markedly attenuating liver fibrosis. Addition of exogenous recombinant Galectin-3 in vitro reversed this abnormality. The reduction in hepatic fibrosis observed in the Galectin-3(-/-) mouse occurred despite equivalent liver injury and inflammation, and similar tissue expression of TGF-beta. TGF-beta failed to transactivate Galectin-3(-/-) hepatic stellate cells, in contrast with WT hepatic stellate cells; however, TGF-beta-stimulated Smad-2 and -3 activation was equivalent. These data suggest that Galectin-3 is required for TGF-beta mediated myofibroblast activation and matrix production. Finally, in vivo siRNA knockdown of Galectin-3 inhibited myofibroblast activation after hepatic injury and may therefore provide an alternative therapeutic approach to the prevention and treatment of liver fibrosis.
Centre for Inflammation Research, Queens Medical Research Institute, University of Edinburgh, 51 Little France Crescent, EH16 4SA Edinburgh, Scotland, United Kingdom.
Neil C
NC
Henderson
Alison C
AC
Mackinnon
Sarah L
SL
Farnworth
Francoise
F
Poirier
Francesco P
FP
Russo
John P
JP
Iredale
Christopher
C
Haslett
Kenneth J
KJ
Simpson
Tariq
T
Sethi
D000818:Animals; D002251:Carbon Tetrachloride / Q000494:pharmacology; D005347:Fibroblasts; D037502:Galectin 3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008106:Liver Cirrhosis, Experimental; D051379:Mice; D018345:Mice, Knockout; D032342:Muscle Cells / Q000378:metabolism* / Q000473:pathology*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015854:Up-Regulation
D037502:Galectin 3; D034741:RNA, Small Interfering; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D002251:Carbon Tetrachloride