Abstract
BackgroundGeranylgeranylacetone (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.MethodsLX2, 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).ResultsGGA 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.ConclusionsGGA 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.
Highlights
Geranylgeranylacetone (GGA), an anti-ulcer drug widely used in Japan, has attracted interest because of its various therapeutic effects
GGA decreased density of hepatic stellate cells (HSCs) We monitored LX2 cells treated with GGA using phasecontrast microscopy and observed a concentrationdependent decrease in cell density (Fig. 1)
Collectively, the results of the present study suggest that GGA could induce apoptosis in HSCs in multifactorial mechanisms and facilitate the attenuation of fibrogenic activity without severe adverse effects in vivo
Summary
Geranylgeranylacetone (GGA), an anti-ulcer drug widely used in Japan, has attracted interest because of its various therapeutic effects. We investigated the effects of GGA on human hepatic stellate cells (HSCs) in vitro and in a mouse model of liver fibrosis. Inhibiting HSC activation is essential for the effective treatment of hepatic fibrosis. ER stress has been reported to induce fibrogenic activity in HSCs [10], but other studies found that HSC death occurred through ER stress–mediated apoptosis [11, 12]. These findings suggest that HSC fate may depend on the magnitude and type of activated stress in the ER. To elucidate the mechanisms of hepatic fibrosis with the goal of developing new therapeutic options, further research on the identification of effective and safe antifibrogenic agents is crucial
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