The interruption of the PDGF and EGF signaling pathways by curcumin stimulates gene expression of PPARγ in rat activated hepatic stellate cell in vitro

Abstract

Activation of hepatic stellate cells (HSC), the major effector in hepatic fibrogenesis, is coupled with sequential alterations in expression of genes, including the upregulation of platelet-derived growth factor-b receptor (PDGF-bR) and epidermal growth factor receptor (EGFR), as well as the down-regulation of the peroxisome proliferator-activated receptor-g (PPARg). However, the relationship among the alterations in expression of the genes and the activation of their signaling in activated HSC remains obscure. We recently showed that curcumin, the yellow pigment in curry, inhibited cell growth and induced gene expression of endogenous PPARg in activated HSC in vitro. The present study is to elucidate the underlying mechanisms, focusing on the impacts of PDGF and EGF signaling. It is hypothesized that the interruption of the PDGF and EGF signaling pathways by curcumin might stimulate gene expression of PPARg in activated HSC. Our results in this report indicate that the activation of PDGF or EGF signaling by exogenous PDGF or EGF inhibits PPARg gene expression in passaged HSC. Curcumin interrupts PDGF and EGF signaling demonstrated by inhibiting tyrosine phosphorylation of PDGF-bR and EGFR and by reducing the levels of phosphorylated phosphatidylinositol-3 kinase (PI-3K/ AKT), extracellular signal-regulated kinase (ERK) and the Jun N-terminal kinase (JNK). The blockade of PI-3K/AKT, ERK or JNK signaling negatively regulates PPARg gene expression in activated HSC, leading to the reduction in cell growth, including inducing cell arrest and apoptosis. Our results collectively demonstrate that the interruption of the PDGF and EGF signaling pathways by curcumin stimulates gene expression of PPARg in activated HSC. These results provide novel insights into the mechanisms of curcumin in the induction of PPARg gene expression in activated HSC.

Curcumin Protects the Rat Liver from CCl4-Caused Injury and Fibrogenesis by Attenuating Oxidative Stress and Suppressing Inflammation

“…The process of HSC activation is associated with sequential up-regulation of corresponding receptors, including PDGF-␤R (Pinzani et al, 1996), EGFR Kömü ves et al, 2000), and type I and II TGF-␤ receptors . We previously demonstrated that curcumin significantly suppressed gene expression of PDGF-␤R, EGFR, and type I and II TGF-␤ receptors in HSC in vitro Chen, 2004, 2006;Zhou et al, 2007). Results in this report further confirmed the in vivo effect of curcumin on the suppression of expression of these genes in the CCl 4 rat model demonstrated by real-time PCR analyses and immunohistochemical assays.…”

“…Further studies demonstrated that curcumin induced gene expression of PPAR␥ in activated HSC in vitro, leading to the activation of PPAR␥ signaling. The latter is a prerequisite for curcumin to inhibit HSC activation Chen, 2004, 2006;Zhou et al, 2007). The current study evaluates the in vivo role of curcumin in the protection of the liver from injury and fibrogenesis caused by carbon tetrachloride (CCl 4 ) in a rat model and further explores the underlying mechanisms.…”

Curcumin limits the fibrogenic evolution of experimental steatohepatitis

“…33 In addition, curcumin blocked the activation of critical pro-fibrogenic pathways in rodent HSCs, including the activation of NF-kB and extracellular signalregulated kinase, propagation of signal transduction downstream of TGF-b receptors, and expression and signaling of PDGF-b receptor and EGF receptor. [33][34][35] These data indicate that curcumin may be a general inhibitor of fibrogenesis independent of the setting in which it develops. In this study, a direct effect on HSCs is suggested by the fact that expression of a-smooth muscle actin, a classical marker of fibrogenic cells derived from the activation of HSCs, was significantly reduced in mice receiving curcumin, and was associated with reduced expression of type I procollagen.…”

Acupuncture Combined with Curcumin Disrupts Platelet-Derived Growth Factor β Receptor/Extracellular Signal-Regulated Kinase Signalling and Stimulates Extracellular Matrix Degradation in Carbon Tetrachloride-Induced Hepatic Fibrosis in Rats

“…8 However, the molecular basis for acupuncture benefits and the coordinated effect was not elucidated. In addition, our previous studies revealed that the PDGF signalling pathway in activated HSCs could be disrupted by curcumin resulting in decreased collagen production in vitro, 9 but the in vivo effects were still unknown. We thus hypothesised that acupuncture at LR3, LR14, BL18 and ST36 combined with curcumin could interfere with the profibrogenic PDGF signal transduction in the fibrotic liver and affect the ECM regulation system, leading to beneficial effects on liver fibrosis.…”