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LEFTY2 alleviates hepatic stellate cell activation and liver fibrosis by regulating the TGF-β1/Smad3 pathway.
Mol Immunol. 2020 10; 126:31-39.MI

Abstract

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.

Authors+Show Affiliations

School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China; Department of Clinical Pharmacology, Second Hospital of Anhui Medical University, 678 Furong Road, Hefei, 230601, Anhui, China.School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China.School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China.School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China.School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China.School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China.School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China.School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China.School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China. Electronic address: lj@ahmu.edu.cn.

Pub Type(s)

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

Language

eng

PubMed ID

32745796

Citation

Yang, Ya-Ru, et al. "LEFTY2 Alleviates Hepatic Stellate Cell Activation and Liver Fibrosis By Regulating the TGF-β1/Smad3 Pathway." Molecular Immunology, vol. 126, 2020, pp. 31-39.
Yang YR, Bu FT, Yang Y, et al. LEFTY2 alleviates hepatic stellate cell activation and liver fibrosis by regulating the TGF-β1/Smad3 pathway. Mol Immunol. 2020;126:31-39.
Yang, Y. R., Bu, F. T., Yang, Y., Li, H., Huang, C., Meng, X. M., Zhang, L., Lv, X. W., & Li, J. (2020). LEFTY2 alleviates hepatic stellate cell activation and liver fibrosis by regulating the TGF-β1/Smad3 pathway. Molecular Immunology, 126, 31-39. https://doi.org/10.1016/j.molimm.2020.07.012
Yang YR, et al. LEFTY2 Alleviates Hepatic Stellate Cell Activation and Liver Fibrosis By Regulating the TGF-β1/Smad3 Pathway. Mol Immunol. 2020;126:31-39. PubMed PMID: 32745796.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - LEFTY2 alleviates hepatic stellate cell activation and liver fibrosis by regulating the TGF-β1/Smad3 pathway. AU - Yang,Ya-Ru, AU - Bu,Fang-Tian, AU - Yang,Yang, AU - Li,Hao, AU - Huang,Cheng, AU - Meng,Xiao-Ming, AU - Zhang,Lei, AU - Lv,Xiong-Wen, AU - Li,Jun, Y1 - 2020/08/01/ PY - 2020/01/07/received PY - 2020/05/23/revised PY - 2020/07/08/accepted PY - 2020/8/4/pubmed PY - 2020/11/11/medline PY - 2020/8/4/entrez KW - ECM KW - HSC KW - LEFTY2 KW - Liver fibrosis KW - Myofibroblasts KW - TGF-β1/Smad3 SP - 31 EP - 39 JF - Molecular immunology JO - Mol Immunol VL - 126 N2 - 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. SN - 1872-9142 UR - https://www.unboundmedicine.com/medline/citation/32745796/LEFTY2_alleviates_hepatic_stellate_cell_activation_and_liver_fibrosis_by_regulating_the_TGF_β1/Smad3_pathway_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0161-5890(20)30419-3 DB - PRIME DP - Unbound Medicine ER -