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Toxicol Appl Pharmacol. 2015 Dec 1;289(2):163-76. doi: 10.1016/j.taap.2015.09.028. Epub 2015 Oct 3.

Silent information regulator 1 (SIRT1) ameliorates liver fibrosis via promoting activated stellate cell apoptosis and reversion.

Author information

  • 1School of Pharmacy, Anhui Medical University, Meishan Road, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University (AMU), China; Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China. Electronic address: wuyuting1302@sina.com.
  • 2School of Pharmacy, Anhui Medical University, Meishan Road, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University (AMU), China; Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China.
  • 3School of Pharmacy, Anhui Medical University, Meishan Road, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University (AMU), China; Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China. Electronic address: lj@ahmu.edu.cn.

Abstract

SIRT1 (silent information regulator 1), a conserved NAD+-dependent histone deacetylase, is closely related with various biological processes. Moreover, the important role of SIRT1 in alcoholic liver disease, nonalcoholic fatty liver and HCC had been widely reported. Recently, a novel role of SIRT1 was uncovered in organ fibrosis diseases. Here, we investigated the inhibitory effect of SIRT1 in liver fibrogenesis. SIRT1 protein was dramatically decreased in CCl4-treated mice livers. Stimulation of LX-2 cells with TGF-β1 also resulted in a significant suppression of SIRT1 protein. Nevertheless, TGF-β1-induced LX-2 cell activation was inhibited by SIRT1 plasmid, and this was accompanied by up-regulation of cell apoptosis-related proteins. Overexpression of SIRT1 also attenuated TGF-β1-induced expression of myofibroblast markers α-SMA and COL1a. However, the important characteristic of the recovery of liver fibrosis is not only the apoptosis of activated stellate cells but also the reversal of the myofibroblast-like phenotype to a quiescent-like phenotype. Restoration of SIRT1 protein was observed in the in vivo spontaneously liver fibrosis reversion model and in vitro MDI (isobutylmethylxanthine, dexamethasone, and insulin)-induced reversed stellate cells, and forced expression of SIRT1 also promoted the reversal of activated stellate cells. Furthermore, lncRNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) was increased in liver fibrosis. RNAi-mediated suppression of MALAT1 resulted in a decrease of myofibroblast markers and restoration of SIRT1 protein. These observations suggested that SIRT1 contributed to apoptosis and reversion of activated LX-2 cells and SIRT1 might be regulated by MALAT1 in liver fibrosis. Therefore, SIRT1 could be considered as a valuable therapeutic target for translational studies of liver fibrosis.

KEYWORDS:

Apoptosis; Liver fibrosis; MALAT1; Reversion; SIRT1

PMID:
26435214
DOI:
10.1016/j.taap.2015.09.028
[PubMed - indexed for MEDLINE]

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