Activation of peroxisome proliferator-activated receptor-γ by curcumin blocks the signaling pathways for PDGF and EGF in hepatic stellate cells
Activation of peroxisome proliferator-activated receptor-γ by curcumin blocks the signaling pathways for PDGF and EGF in hepatic stellate cells
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DOI：
10.1038/labinvest.2008.20
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发表时间：
2008-05-01
影响因子：
5
通讯作者：
Chen, Anping
中科院分区：
文献类型：
--
作者：
Lin, Jianguo;Chen, Anping
在肝纤维化形成过程中，过氧化物酶体增殖物激活受体-g（PPAR γ）丰度的减少伴随着肝星状细胞（HSC）中血小板衍生生长因子（PDGF）和表皮生长因子（EGF）的促有丝分裂信号的激活，HSC是主要的效应细胞。我们以前报道，姜黄素，咖喱中的黄色色素，中断PDGF和EGF信号，刺激PPARg基因表达，并增强其活性，导致体外和体内激活的HSC的细胞增殖抑制。本研究的目的是阐明潜在的机制。我们推测姜黄素增强PPARg活性可能导致PDGF和EGF信号传导中断。我们的实验表明，姜黄素，不同的治疗策略，显示出不同的效率抑制PDGF或EGF刺激的HSC增殖。进一步的实验观察到，姜黄素剂量依赖性地降低PDGF和EGF受体（即PDGF-β R和EGFR）的基因表达，这需要PPARg激活。激活PPARg可抑制HSC中PDGF-β r和EGFR的表达。此外，姜黄素降低了PDGF-β R和EGFR的磷酸化水平，以及它们的下游信号级联，包括ERK 1/2和JNK 1/2。此外，激活PPARg诱导谷氨酸-半胱氨酸连接酶的基因表达，谷氨酸-半胱氨酸连接酶是主要细胞内抗氧化剂谷胱甘肽从头合成的限速酶。姜黄素抑制活化HSC中pdgf-beta r和egfr表达需要谷胱甘肽的从头合成。我们的研究结果共同表明，通过姜黄素增强PPARg活性，通过降低PDGF-β R和EGFR的磷酸化水平，并通过抑制受体基因表达，中断了活化HSC中的PDGF和EGF信号传导。这些结果为姜黄素抑制HSC活化和抑制肝纤维化的机制提供了新的见解。
During hepatic fibrogenesis, reduction in the abundance of peroxisome proliferator-activated receptor-g (PPAR gamma) is accompanied by activation of mitogenic signaling for platelet-derived growth factor ( PDGF) and epidermal growth factor (EGF) in hepatic stellate cells (HSCs), the major effector cells. We previously reported that curcumin, the yellow pigment in curry, interrupted PDGF and EGF signaling, stimulated PPARg gene expression, and enhanced its activity, leading to inhibition of cell proliferation of activated HSC in vitro and in vivo. The aim of this study was to elucidate the underlying mechanisms. We hypothesized that the enhancement of PPARg activity by curcumin might result in the interruption of PDGF and EGF signaling. Our experiments demonstrated that curcumin, with different treatment strategies, showed different efficiencies in the inhibition of PDGF- or EGF-stimulated HSC proliferation. Further experiments observed that curcumin dose dependently reduced gene expression of PDGF and EGF receptors (ie, PDGF-beta R and EGFR), which required PPARg activation. The activation of PPARg by its agonist suppressed pdgf-beta r and egfr expression in HSC. In addition, curcumin reduced the phosphorylation levels of PDGF-beta R and EGFR, as well as their downstream signaling cascades, including ERK1/2 and JNK1/2. Moreover, activation of PPARg induced gene expression of glutamate-cysteine ligase, the rate-limiting enzyme in de novo synthesis of the major intracellular antioxidant, glutathione. De novo synthesis of glutathione was required for curcumin to suppress pdgf-beta r and egfr expression in activated HSCs. Our results collectively demonstrated that enhancement of PPARg activity by curcumin interrupted PDGF and EGF signaling in activated HSCs by reducing the phosphorylation levels of PDGF-beta R and EGFR, and by suppressing the receptor gene expression. These results provide novel insights into the mechanisms of curcumin in the inhibition of HSC activation and the suppression of hepatic fibrogenesis.