LEFTY2 alleviates hepatic stellate cell activation and liver fibrosis by regulating the TGF-β1/Smad3 pathway.

Activated hepatic stellate cells (HSCs) are the major cell type involved in the deposition of extracellular matrix (ECM) during the development of hepatic fibrosis. In this study, we revealed that left-right determination factor 2 (LEFTY2), one of the proteins belonging to the transforming growth factor-β (TGF-β) protein superfamily, was remarkedly decreased in human hepatic fibrosis tissues and in a carbon tetrachloride (CCl4)-induced liver fibrosis mouse model. In addition, TGF-β1 treatment markedly reduced the level of LEFTY2 in HSCs. Importantly, overexpression of LEFTY2 suppressed the activation and proliferation of HSCs. LEFTY2 inhibited the expression of TGF-β1-induced fibrosis-associated genes (α-SMA and COL1a1) in human (LX-2) and rat (HSC-T6) HSC cell lines in vitro. Mechanistically, we demonstrated, for the first time, the role of LEFTY2 in inhibiting TGF-β1/Smad3 signaling, suggesting that there is a mutual antagonism between LEFTY2 and TGF-β1/Smad3 signaling during liver fibrosis. Similarly, we observed that LEFTY2 has a negative effect on its downstream genes, including c-MYC, CDK4, and cyclin D1, in liver fibrosis. Collectively, our data strongly indicated that LEFTY2 plays an important role in controlling the proliferation and activation of HSCs in the progression of liver fibrosis and this could be a potential therapeutic target for its treatment.

Yang YR ，Bu FT ，Yang Y ，Li H ，Huang C ，Meng XM ，Zhang L ，Lv XW ，Li J ... -  《-》

Bone morphogenetic protein-7 represses hepatic stellate cell activation and liver fibrosis via regulation of TGF-β/Smad signaling pathway.

Zou GL ，Zuo S ，Lu S ，Hu RH ，Lu YY ，Yang J ，Deng KS ，Wu YT ，Mu M ，Zhu JJ ，Zeng JZ ，Zhang BF ，Wu X ，Zhao XK ，Li HY ... -  《-》

HOXC8/TGF-β1 positive feedback loop promotes liver fibrosis and hepatic stellate cell activation via activating Smad2/Smad3 signaling.

Liver fibrosis occurs in any chronic liver disease, where extraordinary increase of extracellular matrix components is caused by the hepatic stellate cell (HSC) activation. HOXC8 has been disclosed to participate inregulating cell proliferation and fibrosis in tumors. However, the role of HOXC8 in liver fibrosis and the underlying molecular mechanisms has not yet been investigated. In this study, we founded that HOXC8 mRNA and protein was elevated in a carbon tetrachloride (CCl4)-induced liver fibrosis mouse model and transforming growth factor-β (TGF-β)-treated human (LX-2) HSC cells. Importantly, we observed that downregulating HOXC8 alleviates liver fibrosis and suppressed the fibrogenic gene induction induced by CCl4 in vivo. In addition, inhibition of HOXC8 suppressed the HSC activation and the expression of fibrosis-associated genes (α-SMA and COL1a1) induced by TGF-β1 in LX-2 cells in vitro, while HOXC8 overexpression had the opposite effects. Mechanistically, we demonstrated HOXC8 activates TGFβ1 transcription and enhanced the phosphorylated Smad2/Smad3 levels, suggesting a positive feedback loop between HOXC8 and TGF-β1 that facilitates TGF-β signaling and subsequent HSCs activation. Collectively, our data strongly indicated that a HOXC8/TGF-β1 positive feedback loop plays as a critical role in controlling the HSC activation and in the liver fibrosis process, suggesting that inhibition of HOXC8 may serve as a promoting therapeutic strategy for diseases characterized by liver fibrosis.

Zhang N ，Guo F ，Song Y 《-》

Ampelopsin attenuates carbon tetrachloride-induced mouse liver fibrosis and hepatic stellate cell activation associated with the SIRT1/TGF-β1/Smad3 and autophagy pathway.

Ampelopsin (Amp), a natural flavonoid found in the vine tea of Ampelopsis grossedentata, exhibited anti-cancer, anti-oxidant, anti-inflammatory, anti-apoptosis and hepatoprotective properties. The current study instigates the protective effect of Amp on carbon tetrachloride (CCl4)-induced hepatic fibrosis and explores its underlying mechanisms. The results indicated Amp decreased the levels of liver injury markers. Amp inhibited liver fibrosis, as indicated by decreases in hepatic collagen deposition, extracellular matrix (ECM) deposition and α-smooth muscle actin (α-SMA). Amp blocked the activation of hepaticstellate cells (HSCs) by decreasing the expression of collage I, α-SMA, tissue inhibitor of matrix metalloproteinases (TIMPs) 1, transforming growth factor (TGF)-β1, phosphorylated Smad3 (p-Smad3) and increasing the expression of matrix metalloproteinases (MMPs) 9 and SIRT1 in the model of liver fibrosis and cultured HSCs. The sirtuin 1 (SIRT1) specific inhibitor Sirtinol activated the TGF-β1/Smad3 pathway and enhanced ECM accumulation. Attractively, Amp up-regulates the expression of autophagy-related proteins microtubule-associated protein light chain three II (LC3-II) and Beclin-1 in vivo and in vitro. However, depletion of autophagy by specific inhibitor 3-MA obviously abolished the inhibiting effect of Amp on HSC activation and hepatic fibrosis. Conclusively, these results suggest that Amp could decrease CCl4-induced hepatic fibrosis through regulating the SIRT1/TGF-β1/Smad3 and autophagy pathway.

Ma JQ ，Sun YZ ，Ming QL ，Tian ZK ，Yang HX ，Liu CM ... -  《-》

Sauchinone attenuates liver fibrosis and hepatic stellate cell activation through TGF-β/Smad signaling pathway.

Hepatic stellate cells (HSCs) are key mediators of fibrogenesis, and the regulation of their activation is now viewed as an attractive target for the treatment of liver fibrosis. Here, the authors investigated the ability of sauchinone, an active lignan found in Saururus chinensis, to regulate the activation of HSCs, to prevent liver fibrosis, and to inhibit oxidative stress in vivo and in vitro. Blood biochemistry and histopathology were assessed in CCl4-induced mouse model of liver fibrosis to investigate the effects of sauchinone. In addition, transforming growth factor-β1 (TGF-β1)-activated LX-2 cells (a human HSC line) were used to investigate the in vitro effects of sauchinone. Sauchinone significantly inhibited liver fibrosis, as indicated by decreases in regions of hepatic degeneration, inflammatory cell infiltration, and the intensity of α-smooth muscle actin staining in mice. Sauchinone blocked the TGF-β1-induced phosphorylation of Smad 2/3 and the transcript levels of plasminogen activator inhibitor-1 and matrix metalloproteinase-2 as well as autophagy in HSCs. Furthermore, sauchinone inhibited oxidative stress, as assessed by stainings of 4-hydroxynonenal and nitrotyrosine: these events may have a role in its inhibitory effects on HSCs activation. Sauchinone attenuated CCl4-induced liver fibrosis and TGF-β1-induced HSCs activation, which might be, at least in part, mediated by suppressing autophagy and oxidative stress in HSCs.

Lee JH ，Jang EJ ，Seo HL ，Ku SK ，Lee JR ，Shin SS ，Park SD ，Kim SC ，Kim YW ... -  《-》