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Profibrogenic transforming growth factor-beta/activin receptor-like kinase 5 signaling via connective tissue growth factor expression in hepatocytes.
Hepatology. 2007 Oct; 46(4):1257-70.Hep

Abstract

Connective tissue growth factor (CTGF) is important for transforming growth factor-beta (TGF-beta)-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-beta. TGF-beta-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-beta transgenic mice correlated with serum TGF-beta levels. Smad7 overexpression in cultured hepatocytes abrogated TGF-beta-dependent and intrinsic CTGF expression, indicating that TGF-beta 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-beta 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 TGF-beta antagonist Smad7.

Authors+Show Affiliations

Molecular Alcohol Research in Gastroenterology, Department of Medicine II, Faculty of Medicine at Mannheim, University of Heidelberg, Mannheim, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17657819

Citation

Weng, Hong-Lei, et al. "Profibrogenic Transforming Growth Factor-beta/activin Receptor-like Kinase 5 Signaling Via Connective Tissue Growth Factor Expression in Hepatocytes." Hepatology (Baltimore, Md.), vol. 46, no. 4, 2007, pp. 1257-70.
Weng HL, Ciuclan L, Liu Y, et al. Profibrogenic transforming growth factor-beta/activin receptor-like kinase 5 signaling via connective tissue growth factor expression in hepatocytes. Hepatology. 2007;46(4):1257-70.
Weng, H. L., Ciuclan, L., Liu, Y., Hamzavi, J., Godoy, P., Gaitantzi, H., Kanzler, S., Heuchel, R., Ueberham, U., Gebhardt, R., Breitkopf, K., & Dooley, S. (2007). Profibrogenic transforming growth factor-beta/activin receptor-like kinase 5 signaling via connective tissue growth factor expression in hepatocytes. Hepatology (Baltimore, Md.), 46(4), 1257-70.
Weng HL, et al. Profibrogenic Transforming Growth Factor-beta/activin Receptor-like Kinase 5 Signaling Via Connective Tissue Growth Factor Expression in Hepatocytes. Hepatology. 2007;46(4):1257-70. PubMed PMID: 17657819.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Profibrogenic transforming growth factor-beta/activin receptor-like kinase 5 signaling via connective tissue growth factor expression in hepatocytes. AU - Weng,Hong-Lei, AU - Ciuclan,Loredana, AU - Liu,Yan, AU - Hamzavi,Jafar, AU - Godoy,Patricio, AU - Gaitantzi,Haristi, AU - Kanzler,Stefan, AU - Heuchel,Rainer, AU - Ueberham,Uwe, AU - Gebhardt,Rolf, AU - Breitkopf,Katja, AU - Dooley,Steven, PY - 2007/7/28/pubmed PY - 2007/12/6/medline PY - 2007/7/28/entrez SP - 1257 EP - 70 JF - Hepatology (Baltimore, Md.) JO - Hepatology VL - 46 IS - 4 N2 - UNLABELLED: Connective tissue growth factor (CTGF) is important for transforming growth factor-beta (TGF-beta)-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-beta. TGF-beta-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-beta transgenic mice correlated with serum TGF-beta levels. Smad7 overexpression in cultured hepatocytes abrogated TGF-beta-dependent and intrinsic CTGF expression, indicating that TGF-beta 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-beta 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 TGF-beta antagonist Smad7. SN - 0270-9139 UR - https://www.unboundmedicine.com/medline/citation/17657819/Profibrogenic_transforming_growth_factor_beta/activin_receptor_like_kinase_5_signaling_via_connective_tissue_growth_factor_expression_in_hepatocytes_ L2 - https://doi.org/10.1002/hep.21806 DB - PRIME DP - Unbound Medicine ER -