Signal Transducer and Activator of Transcription 3 Protects From Liver Injury and Fibrosis in a Mouse Model of Sclerosing Cholangitis

Mair, Markus; Zollner, Gernot; Schneller, Doris; Musteanu, Mónica; Fickert, Peter; Gumhold, J.; Schuster, Christian; Fuchsbichler, Andrea; Bilban, Martin; Tauber, Stefanie; Esterbauer, Harald; Kenner, Lukas; Poli, Valeria; Blaas, Leander; Kornfeld, Jan-Wilhelm; Casanova, Emilio; Mikulits, Wolfgang; Trauner, Michael; Eferl, Robert

doi:10.1053/j.gastro.2010.02.049

Cited by 69 publications

(84 citation statements)

References 36 publications

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“…The role of STAT3 in liver inflammation and fibrosis is cell type-specific and model-dependent. STAT3 activation in hepatocytes induces acute phase responses, promoting liver regeneration, hepatocyte survival, and ameliorating fatty liver (8,13). In hepatocyte-specific STAT3 knockout mice, CCl 4 injection induced greater liver damage than wild-type mice (14).…”

Section: Discussionmentioning

confidence: 99%

Sorafenib and its derivative SC-1 exhibit antifibrotic effects through signal transducer and activator of transcription 3 inhibition

Shiau²,

Jao

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Signal transducer and activator of transcription 3 (STAT3) had been involved in liver fibrogenesis. We aimed to explore the antifibrotic activities of sorafenib and its derivative SC-1 (devoid of Raf kinase inhibition activity) both in vivo and in vitro with special focus on the STAT3 pathway in hepatic stellate cells (HSCs). The clinical role of STAT3 in chronic hepatitis B (CHB) was also investigated. Experimental fibrosis mouse models were established by thioacetamide injection and bile duct ligation in Balb/C mice and treated with sorafenib and SC-1. Rat and human HSCs were used for mechanistic investigations. Forty CHB patients were enrolled to quantify the hepatic phospho-STAT3 (p-STAT3) levels and correlated with liver fibrosis. Both sorafenib and SC-1 ameliorated liver fibrosis in vivo and promoted HSC apoptosis in vitro. p-STAT3 and downstream signals were down-regulated after sorafenib and SC-1 treatment in HSC. STAT3 overexpression in HSC enhanced cell proliferation and undermined the apoptotic effects of sorafenib and SC-1, whereas STAT3-specific inhibition promoted HSC apoptosis. Sorafenib and SC-1 activated Src-homology protein tyrosine phosphatase-1 (SHP-1) and STAT3 inhibition followed. Of particular interest, in CHB patients with advanced liver fibrosis, p-STAT3 in HSC was significantly overexpressed and positively correlated with the severity of liver fibrosis and plasma IL-6 levels. In conclusion, sorafenib and SC-1 ameliorate liver fibrosis through STAT3 inhibition in HSC and STAT3 may potentially serve as a promising fibrotic biomarker and target in liver fibrosis. SHP-1 phosphatase-directed STAT3 inhibition may represent a previously unidentified strategy for antifibrotic drug discovery.hepatic stellate cell | STAT3 | SHP-1 | hepatitis B | liver fibrosis

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Section: Discussionmentioning

confidence: 99%

Sorafenib and its derivative SC-1 exhibit antifibrotic effects through signal transducer and activator of transcription 3 inhibition

Shiau²,

Jao

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…p21 is one of the main downstream targets of the tumour suppressor p53 that delays cell cycle progression of cells with DNA damage. In this study, we analysed the molecular events occurring during liver cancer initiation using a well-established mouse model of chronic inflammatory liver injury and hepatocarcinogenesis 24 25. Our data reveal that liver regeneration was significantly impaired and, more importantly, tumour development was profoundly delayed in p21-deficient Mdr2 −/− mice.…”

Section: Discussionmentioning

confidence: 99%

p21 promotes sustained liver regeneration and hepatocarcinogenesis in chronic cholestatic liver injury

Marhenke

Buitrago‐Molina

Endig

et al. 2013

Gut

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“…Bile duct ligation is caused by surgical obstruction of the common bile duct and mimics cholestatic liver disease in patients. Mice deficient in the canalicular phospholipid flippase (Mdr2/Abcb4 -/- mice) spontaneously develop liver injury (PSC; Shimamura et al, 2008), (Fichtner-Feigl et al, 2006; Jinnin et al, 2006; Fickert et al, 2009; Baghdasaryan et al, 2010; Mair et al, 2010; McHedlidze et al, 2013), which resembles PSC and most closely mimics MDR3 deficiency in patients,(Pope et al, 2005) which ranges from familial intrahepatic cholestasis to adult liver cirrhosis. The pathogenesis of liver injury in Mdr2 -/- mice is characterized by disruption of tight junctions and basement membranes of bile ducts, bile leakage into the portal tract, and formation of periportal biliary fibrosis (Jinnin et al, 2006; McHedlidze et al, 2013).…”

Section: Origin Of Hepatic Myofibroblastsmentioning

confidence: 99%

The types of hepatic myofibroblasts contributing to liver fibrosis of different etiologies

et al. 2014

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Liver fibrosis results from dysregulation of normal wound healing, inflammation, activation of myofibroblasts, and deposition of extracellular matrix (ECM). Chronic liver injury causes death of hepatocytes and formation of apoptotic bodies, which in turn, release factors that recruit inflammatory cells (neutrophils, monocytes, macrophages, and lymphocytes) to the injured liver. Hepatic macrophages (Kupffer cells) produce TGFβ1 and other inflammatory cytokines that activate Collagen Type I producing myofibroblasts, which are not present in the normal liver. Secretion of TGFβ1 and activation of myofibroblasts play a critical role in the pathogenesis of liver fibrosis of different etiologies. Although the composition of fibrogenic myofibroblasts varies dependent on etiology of liver injury, liver resident hepatic stellate cells and portal fibroblasts are the major source of myofibroblasts in fibrotic liver in both experimental models of liver fibrosis and in patients with liver disease. Several studies have demonstrated that hepatic fibrosis can reverse upon cessation of liver injury. Regression of liver fibrosis is accompanied by the disappearance of fibrogenic myofibroblasts followed by resorption of the fibrous scar. Myofibroblasts either apoptose or inactivate into a quiescent-like state (e.g., stop collagen production and partially restore expression of lipogenic genes). Resolution of liver fibrosis is associated with recruitment of macrophages that secrete matrix-degrading enzymes (matrix metalloproteinase, collagenases) and are responsible for fibrosis resolution. However, prolonged/repeated liver injury may cause irreversible crosslinking of ECM and formation of uncleavable collagen fibers. Advanced fibrosis progresses to cirrhosis and hepatocellular carcinoma. The current review will summarize the role and contribution of different cell types to populations of fibrogenic myofibroblasts in fibrotic liver.

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Signal Transducer and Activator of Transcription 3 Protects From Liver Injury and Fibrosis in a Mouse Model of Sclerosing Cholangitis

Cited by 69 publications

References 36 publications

Sorafenib and its derivative SC-1 exhibit antifibrotic effects through signal transducer and activator of transcription 3 inhibition

Sorafenib and its derivative SC-1 exhibit antifibrotic effects through signal transducer and activator of transcription 3 inhibition

p21 promotes sustained liver regeneration and hepatocarcinogenesis in chronic cholestatic liver injury

The types of hepatic myofibroblasts contributing to liver fibrosis of different etiologies

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