Conditional Tetracycline–Regulated Expression of Tgf–β1 in Liver of Transgenic Mice Leads to Reversible Intermediary Fibrosis

Ueberham, Elke

doi:10.1053/jhep.2003.50196

Cited by 140 publications

(141 citation statements)

References 44 publications

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“…4 TGF-␤ and its family members have been implicated in liver apoptosis and in liver regeneration. 5,[40][41][42][43][44] Our data show a slight increase in TGF-␤ in the MMP-9 Ϫ/Ϫ animals throughout the time studied; however, the lack of statistical differences despite changes in morphology and regeneration rate indicate that MMP-9 does not affect TGF-␤1 and may depend on additional factors or cytokines. 45 HGF is a critically important mediator during liver regeneration; it is expressed as a single-chain unprocessed protein that can bind the extracellular matrix and is processed by urokinase plasminogen activator or HGF activator into ␣ and ␤ chains.…”

Section: Discussionmentioning

confidence: 97%

Matrix metalloproteinase-9 is an important factor in hepatic regeneration after partial hepatectomy in mice

et al. 2006

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Partial hepatectomy triggers hepatocyte proliferation, hepatic matrix remodeling, and hepatocyte apoptosis, all of which are important processes in the regenerating liver. Previous studies have shown an increase in the levels of matrix metalloproteinases gelatinase A (MMP-2) and gelatinase B (MMP-9) after partial hepatectomy. The goal of this study was to investigate the role of MMP-9 in liver regeneration after partial hepatectomy. A 70% hepatectomy or sham laparotomy was performed in wild-type or MMP-9 -deficient (MMP-9 ؊/؊ ) mice. Hepatic regeneration was determined by liver weight/total body weight ratios and BrdU staining, which was used to a calculate mitotic index at several times postoperatively. Cytokine and growth factor expression was evaluated by Luminex™ bead-based ELISA and Western blots. Finally, the effect of MMP-9 on apoptosis was measured using TUNEL and caspase expression. The MMP-9 ؊/؊ animals had a delayed hepatic regenerative response when compared with wild-type controls. The MMP-9 -deficient animals expressed significantly less VEGF, HGF, and TNF-␣ between days 2 and 3 post-hepatectomy. Apoptosis, as measured by TUNEL staining and caspase expression, was decreased in the MMP-9 ؊/؊ . In conclusion, MMP-9 plays an important role in liver regeneration after partial hepatectomy by affecting matrix remodeling, as well as cytokine, growth factor, and caspase expression.

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Section: Discussionmentioning

confidence: 97%

Matrix metalloproteinase-9 is an important factor in hepatic regeneration after partial hepatectomy in mice

et al. 2006

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“…Among the numerous profibrogenic mediators, TGF-β is regarded as the most potent in liver fibrosis. Overexpression of TGF-β in the liver has been shown to induce severe liver fibrosis [22], whereas disrupting its synthesis or signaling pathway markedly decreased fibrosis in experimental models [23]. In HSC, TGF-β promotes the activation process, stimulates the synthesis of ECM proteins and inhibits their degradation [24].…”

Section: Discussionmentioning

confidence: 99%

Lipid accumulation in hepatocytes induces fibrogenic activation of hepatic stellate cells

et al. 2009

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Abbreviations: CM (conditioned medium); FFAs (free fatty acids); HSC (hepatic stellate cells); NAFLD (non-alcoholic fatty liver disease); NASH (non-alcoholic steatohepatitis); MMP (matrix-metallo-proteinase); NFκB (nuclear-factor κB); PHH (primary human hepatocytes); TIMP-1/-2 (tissue inhibitor of metallo-proteinase-1/-2) Despite the initial belief that non-alcoholic fatty liver disease is a benign disorder, it is now recognized that fibrosis progression occurs in a significant number of patients. Furthermore, hepatic steatosis has been identified as a risk factor for the progression of hepatic fibrosis in a wide range of other liver diseases. Here, we established an in vitro model to study the effect of hepatic lipid accumulation on hepatic stellate cells (HSCs), the central mediators of liver fibrogenesis. Primary human hepatocytes were incubated with the saturated fatty acid palmitate to induce intracellular lipid accumulation. Subsequently, human HSCs were incubated with conditioned media (CM) from steatotic or control hepatocytes. Lipid accumulation in hepatocytes induced the release of factors that accelerated the activation and proliferation of HSC, and enhanced their resistance to apoptosis, largely mediated via activation of the PI-3-kinase pathway. Furthermore, CM from steatotic hepatocytes induced the expression of the profibrogenic genes TGF-β, tissue inhibitor of metallo-proteinase-1 (TIMP-1), TIMP-2 and matrix-metallo-proteinase-2, as well as nuclear-factor κB-dependent MCP-1 expression in HSC. In summary, our in vitro data indicate a potential mechanism for the pathophysiological link between hepatic steatosis and fibrogenesis in vivo. Herewith, this study provides an attractive in vitro model to study the molecular mechanisms of steatosis-induced fibrogenesis, and to identify and test novel targets for antifibrotic therapies in fatty liver disease.

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“…The generation of double-transgenic mice with conditional liver-specific expression of TGF-␤1 was described. 28 Briefly, for the construction of the TGF-␤1 expression vector, mutated porcine TGF-␤1 minimal complementary DNA (cDNA; kindly provided by Dr. Nashreen Khalil, Manitoba Institute of Cell Biology, Winnipeg, Canada) and pBI-5 (CVU89934; GenBank at NCBI, Bethesda, MD) were used. Transgenic mouse lines were generated by pronuclear injection with standard techniques.…”

Section: Methodsmentioning

confidence: 99%

Profibrogenic transforming growth factor-β/activin receptor–like kinase 5 signaling via connective tissue growth factor expression in hepatocytes

et al. 2007

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Connective tissue growth factor (CTGF) is important for transforming growth factor-␤ (TGF-␤)-induced liver fibrogenesis. Hepatic stellate cells have been recognized as its major cellular source in the liver. Here we demonstrate the induction of CTGF expression in hepatocytes of damaged livers and identify a molecular mechanism responsible for it. CTGF expression was found by immunohistochemistry in bile duct epithelial cells, hepatic stellate cells, and hepatocytes in fibrotic liver tissue from patients with chronic hepatitis B infection. Similarly, CTGF expression was induced in hepatocytes of carbon tetrachloride-treated mice. CTGF expression and secretion were detected spontaneously in a medium of hepatocytes after 3 days of culture, which was enhanced by stimulation with TGF-␤. TGF-␤-induced CTGF expression was mediated through the activin receptor-like kinase 5 (ALK5)/ Smad3 pathway, whereas activin receptor-like kinase 1 activation antagonized this effect. CTGF expression in the liver tissue of TGF-␤ transgenic mice correlated with serum TGF-␤ levels. Smad7 overexpression in cultured hepatocytes abrogated TGF-␤-dependent and intrinsic CTGF expression, indicating that TGF-␤ signaling was required. In line with these data, hepatocyte-specific transgenic Smad7 reduced CTGF expression in carbon tetrachloride-treated animals, whereas in Smad7 knockout mice, it was enhanced. Furthermore, an interferon gamma treatment of patients with chronic hepatitis B virus infection induced Smad7 expression in hepatocytes, leading to decreased CTGF expression and fibrogenesis. Conclusion: Our data provide evidence for the profibrogenic activity of TGF-␤ directed to hepatocytes and mediated via the up-regulation of CTGF. We identify ALK5-dependent Smad3 signaling as the responsible pathway inducing CTGF expression, which can be hindered by an activated activin receptor-like kinase 1 pathway and completely inhibited by

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Conditional Tetracycline–Regulated Expression of Tgf–β1 in Liver of Transgenic Mice Leads to Reversible Intermediary Fibrosis

Cited by 140 publications

References 44 publications

Matrix metalloproteinase-9 is an important factor in hepatic regeneration after partial hepatectomy in mice

Matrix metalloproteinase-9 is an important factor in hepatic regeneration after partial hepatectomy in mice

Lipid accumulation in hepatocytes induces fibrogenic activation of hepatic stellate cells

Profibrogenic transforming growth factor-β/activin receptor–like kinase 5 signaling via connective tissue growth factor expression in hepatocytes

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