title: Expression and function of the atypical cadherin FAT1 in chronic liver disease.
abstract: Hepatic fibrosis can be considered as wound healing process in response to hepatocellular injury. Activation of hepatic stellate cells (HSCs) is a key event of hepatic fibrosis since activated HSCs are the cellular source of enhanced extracellular matrix deposition, and reversion of liver fibrosis is accompanied by clearance of activated HSCs by apoptosis. The atypical cadherin FAT1 has been shown to regulate diverse biological functions as cell proliferation and planar cell polarity, and also to affect wound healing. Here, we found increased FAT1 expression in different murine models of chronic liver injury and in cirrhotic livers of patients with different liver disease. Also in hepatic tissue of patients with non-alcoholic steatohepatitis FAT1 expression was significantly enhanced and correlated with collagen alpha I(1) expression. Immunohistochemistry revealed no significant differences in staining intensity between hepatocytes in normal and cirrhotic liver tissue but myofibroblast like cells in fibrotic septa of cirrhotic livers showed a prominent immunosignal. Furthermore, FAT1 mRNA and protein expression markedly increased during in vitro activation of primary human and murine HSCs. Together, these data indicated activated HSCs as cellular source of enhanced FAT1 expression in diseased livers. To gain insight into the functional role of FAT1 in activated HSCs we suppressed FAT1 in these cells by siRNA. We newly found that FAT1 suppression in activated HSCs caused a downregulation of NFκB activity. This transcription factor is critical for apoptosis resistance of HSCs, and consequently, we detected a higher apoptosis rate in FAT1 suppressed HSCs compared to control cells. Our findings suggest FAT1 as new therapeutic target for the prevention and treatment of hepatic fibrosis in chronic liver disease.
authors.affiliation: Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Valletta
authors.forename: Barbara
authors.initials: B
authors.lastname: Czech
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Thasler
authors.forename: Martina
authors.initials: M
authors.lastname: Müller
authors.forename: Anja-Katrin
authors.initials: AK
authors.lastname: Bosserhoff
authors.forename: Claus
authors.initials: C
authors.lastname: Hellerbrand
mesh_terms: D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D002908:Chronic Disease; D024042:Collagen Type I / Q000096:biosynthesis; D000090602:Collagen Type I, alpha 1 Chain; D004195:Disease Models, Animal; D055166:Hepatic Stellate Cells / Q000378:metabolism*; D006801:Humans; D008103:Liver Cirrhosis / Q000378:metabolism*; D051379:Mice; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D015820:Cadherins; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; C502403:FAT1 protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C502406:fat1 protein, mouse