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Geranylgeranylacetone attenuates fibrogenic activity and induces apoptosis in cultured human hepatic stellate cells and reduces liver fibrosis in carbon tetrachloride-treated mice

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Title: Geranylgeranylacetone attenuates fibrogenic activity and induces apoptosis in cultured human hepatic stellate cells and reduces liver fibrosis in carbon tetrachloride-treated mice
Authors: Senoo, Takemasa / Sasaki, Ryu / Akazawa, Yuko / Ichikawa, Tatsuki / Miuma, Satoshi / Miyaaki, Hisamitsu / Taura, Naota / Nakao, Kazuhiko
Issue Date: 27-Feb-2018
Publisher: BioMed Central Ltd.
Citation: BMC Gastroenterology, 18, 34; 2018
Abstract: Background: Geranylgeranylacetone (GGA), an anti-ulcer drug widely used in Japan, has attracted interest because of its various therapeutic effects. Therefore, we investigated the effects of GGA on human hepatic stellate cells (HSCs) in vitro and in a mouse model of liver fibrosis. Methods: LX2, an immortalized human HSC line, was cultured and treated with GGA at concentrations up to 0.5 mM. After GGA treatment, changes in cellular morphology, apoptosis, and fibrosis-related gene expression were assessed. Male C57BL/6 J mouse model of carbon tetrachloride (CCl4)-induced liver fibrosis was treated with GGA. Liver fibrosis was evaluated using Sirius red staining and immunohistochemistry for α-smooth muscle actin (SMA). Results: GGA decreased the density of LX2 and primary human hepatic stellate cells but not that of HepG2 cells (a human hepatoma cell line), which was employed as control. In addition, GGA decreased the expression of fibrogenic genes and increased that of C/EBP homologous protein (CHOP). It also induced endoplasmic reticulum (ER) stress and increased apoptosis. CHOP knockdown, however, failed to suppress the GGA-induced decrease in LX2 cell density, suggesting the involvement of additional molecules in ER stress-associated apoptosis. Expression of death receptor 5, mitogen-activated protein kinase, heat shock protein 70, and Akt, all of which affect the activity of stellate cells, was unchanged in relation to LX2 cell fibrogenic activity. In the mouse model of liver fibrosis, GGA decreased the extent of Sirius red staining and SMA expression. Conclusions: GGA attenuated fibrogenic activity and induced apoptosis in cultured human HSCs, and suppressed liver fibrosis in mice, suggesting its potential as an agent for treating liver fibrosis.
Keywords: Apoptosis / Geranylgeranylacetone / Hepatic stellate cells / Liver fibrosis
URI: http://hdl.handle.net/10069/38248
DOI: 10.1186/s12876-018-0761-7
Rights: © 2018 The Author(s). This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Type: Journal Article
Text Version: publisher
Appears in Collections:Articles in academic journal

Citable URI : http://hdl.handle.net/10069/38248

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