Title: T1766 Mcl-1 - a Critical Factor for the Survival of Hepatocytes
Abstract: The aim of this study was to elucidate the underlying mechanisms of curcumin in the interruption of PDGF and EGF signaling in HSC.We hypothesized that the enhancement of PPARγ activity by curcumin might result in the interruption of the signaling pathways for PDGF and EGF.RESULTS: PDGF and EGF showed different effects on the stimulation of cell proliferation with or without the 24hr pretreatment of HSC with curcumin.To elucidate the underlying mechanisms, we observed that curcumin dosedependently reduced gene expression of PDGF and EGF receptors (i.e.PDGF βR and EGFR), which was eliminated by inhibiting PPARγ activation.Additional experiments indicated that the activation of PPARγ, by the forced expression of exogenous PPARγ or by the natural PPARγ agonist PGJ2, suppressed gene expression of PDGF-βR and EGFR in activated HSC In Vitro.The activation of PPARγ reduced ERK1/2 and JNK1/2 activities, which was shown to play crucial roles in the curcumin suppression of gene expression of PDGF βR and EGFR in HSC.Further studies revealed that curcumin also reduced the levels of phosphorylation of PDGF-βR and EGFR, as well as their downstream signaling cascades, including ERK1/2 and JNK1/2.Moreover, other experiments indicated that the activation of PPARγ 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 gene expression of PDGF-βR and EGFR in activated HSC.CONCLUSION: Our results demonstrate that the enhancement of PPARγ activity in activated HSC by curcumin antagonistically interrupts the signaling pathways for PDGF and EGF by reducing the level of phosphorylation of PDGF-βR and EGFR and by suppressing gene expression of these receptors.These results provide novel insights into the mechanisms of curcumin in the inhibition of HSC activation and the suppression of hepatic fibrogenesis.
Publication Year: 2008
Publication Date: 2008-04-01
Language: en
Type: article
Indexed In: ['crossref']
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