Geranylgeranylacetone attenuates hepatic fibrosis by increasing the expression of heat shock protein 70

Abstract

Increasing evidence has demonstrated that the heat shock protein 70 (HSP70) gene may be closely associated with tissue fibrosis; however, the association between HSP70 and liver fibrosis remains to be fully elucidated. The present study hypothesized that geranylgeranylacetone (GGA) exerts beneficial effects on liver fibrosis though upregulation of the expression of HSP70. Liver fibrosis was induced in rats using carbon tetrachloride (CCl4). The rats were subsequently divided into three groups: Control group, CCl4 model group and CCl4 model + GGA group. Liver fibrosis in the rats was evaluated using hematoxylin and eosin staining, Masson's trichrome staining and Sirius red staining. The levels of serum alanine aminotransferase, aspartate aminotransferase and total bilirubin were determined using an automated biochemistry analyzer. The levels of total hepatic hydroxyproline were also determined. The expression levels of α-smooth muscle actin (α-SMA) and transforming growth factor-β1 (TGF-β1) were determined using immunofluorescence staining and western blotting, and the protein expression levels of HSP70 were determined using western blotting. The CCl4-induced rats exhibited liver fibrosis, increased hydroxyproline content, impaired liver function, upregulated expression levels of the α-SMA and TGF-β1 pro-fibrogenic proteins, and increased expression of HSP70, compared with the control group. These changes were attenuated by treatment with GGA. These results demonstrated that GGA exerted beneficial effects in CCl4-induced liver fibrosis via upregulating the expression of HSP70.

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

“…The ability of GGA to induce HSP upregulation in several organs is well known [ 25 , 26 ]. Although He et al had indicated that the upregulation of HSP70 by GGA was associated with the suppression of fibrogenesis in the mouse liver [ 16 ], we did not find evidence of GGA-induced HSP70 upregulation in LX2 cells. These discrepancies may have resulted from the difference in the cell lines.…”

“…GGA treatment is known to induce upregulation of HSP family proteins in several organs. Previously, it was shown that GGA treatment in mice upregulated HSP70 levels in a liver specimen and was associated with suppression of liver fibrosis [ 16 ]. Therefore, we measured HSP70 expression in LX2 cells treated with GGA by western blot, and found that treatment with GGA for 24 h did not significantly change HSP70 expression compared to controls (Additional file 1 : SD).…”

“…For example, several studies have demonstrated that GGA has the ability to induce the expression of heat shock protein (HSP) families in various organs, including the liver [ 13 – 15 ]. In vivo, He et al showed that GGA suppressed extracellular matrix (ECM) protein deposition in rat liver specimens and regulated the progression of hepatic fibrosis through the upregulation of HSP70 expression [ 16 ]. Another study showed that GGA induced ER stress in rat mesangial cells [ 17 ].…”

Effects of geranylgeranylacetone upon cardiovascular diseases

“…GGA has been reported to induce overexpression of HSPs in stress conditions, whereas the induction effect is weak in the absence of stimulation, which suggests that GGA has few side effects. It has been demonstrated that GGA elicits multiple organ protection by increasing the expression of HSPs in response to hypoxia, ischemia, oxidation, toxins, and inflammation . In 2001, Ooie et al found that GGA given via the oral route can render cardioprotection against IRI by inducing HSP72 expression in rat hearts.…”

“…It has been demonstrated that GGA elicits multiple organ protection by increasing the expression of HSPs in response to hypoxia, ischemia, oxidation, toxins, and inflammation. [34][35][36][37] In 2001, Ooie et al 19 found that GGA given via the oral route can render cardioprotection against IRI by inducing HSP72 expression in rat hearts. Based on their study, there has been increasing interest in the cardiovascular protective effects and underlying mechanism of action of GGA.…”