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

Abstract

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

Melatonin limits the expression of profibrogenic genes and ameliorates the progression of hepatic fibrosis in mice

“…For example, CTGF is a cytokine induced by TGF-b that acts synergically to promote matrix protein deposition and fibrogenesis, both in vitro and in vivo. 34 Smad3 signaling has been identified as the responsible pathway inducing CTGF expression in hepatocytes of CCl 4 -treated mice, 35 and knockdown of CTGF by injection of small interfering RNA into the portal veins of rat livers prevents CCl 4 -induced fibrosis by inhibiting TGF-b induction and HSC activation. 36 It has been reported that in rats treated with CCl 4 silymarin decreases CTGF to improve liver fibrosis 37 and curcumin significantly attenuates the severity of liver damage through inhibition of CTGF expression.…”

Mechanisms of Hepatic Fibrogenesis

“…134 Although stimulation of CTGF production traditionally has been considered TGFβ-dependent, 135 TGFβ-independent regulation is increasingly likely as well. 136 Moreover, TGFβ stimulates CTGF primarily in hepatocytes, not stellate cells, 137,138 a notable exception to the general rule that cytokine signaling in stellate cell activation typically is autocrine.…”

Alcohol, Signaling, and ECM Turnover

“…Until recently CTGF was accepted to be expressed by activated stellate cells in liver diseases (Paradis et al, 2002). The involvement of CTGF in hepatocytes of hepatitis B virus infected livers as well as in CCL 4 treated mice (Weng et al, 2007) is a novel finding. It is noteworthy that expression of CTGF was mainly mediated by TGF-b ⁄ serine ⁄ threonine kinase receptor (ALK)5⁄ Smad3 signaling, although additional pathways have been described to contribute to TGF-b-mediated CTGF expression in other cells types (Arnott et al, 2008;Woods et al, 2008).…”