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Activation of PPARγ/P53 signaling is required for curcumin to induce hepatic stellate cell senescence

Activation of quiescent hepatic stellate cells (HSCs) is the major event in hepatic fibrogenesis, along with enhancement of cell proliferation and overproduction of extracellular matrix. Although inhibition of cell proliferation and induction of apoptosis are potential strategies to block the activa...

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Autores principales: Jin, H, Lian, N, Zhang, F, Chen, L, Chen, Q, Lu, C, Bian, M, Shao, J, Wu, L, Zheng, S
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4855671/
https://www.ncbi.nlm.nih.gov/pubmed/27077805
http://dx.doi.org/10.1038/cddis.2016.92
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author Jin, H
Lian, N
Zhang, F
Chen, L
Chen, Q
Lu, C
Bian, M
Shao, J
Wu, L
Zheng, S
author_facet Jin, H
Lian, N
Zhang, F
Chen, L
Chen, Q
Lu, C
Bian, M
Shao, J
Wu, L
Zheng, S
author_sort Jin, H
collection PubMed
description Activation of quiescent hepatic stellate cells (HSCs) is the major event in hepatic fibrogenesis, along with enhancement of cell proliferation and overproduction of extracellular matrix. Although inhibition of cell proliferation and induction of apoptosis are potential strategies to block the activation of HSCs, a better understanding of the senescence of activated HSCs can provide a new therapeutic strategy for prevention and treatment of liver fibrosis. The antioxidant curcumin, a phytochemical from turmeric, has been shown to suppress HSC activation in vitro and in vivo. The current work was aimed to evaluate the effect of curcumin on senescence of activated HSCs and to elucidate the underlying mechanisms. In this study, curcumin promoted the expression of senescence marker Hmga1 in rat fibrotic liver. In addition, curcumin increased the number of senescence-associated β-galactosidase-positive HSCs in vitro. At the same time, curcumin induced HSC senescence by elevating the expression of senescence markers P16, P21 and Hmga1, concomitant with reduced abundance of HSC activation markers α-smooth muscle actin and α1(I)-procollagen in cultured HSCs. Moreover, curcumin affected the cell cycle and telomerase activity. We further demonstrated that P53 pharmacological inhibitor pifithrin-α (PFT-α) or transfection with P53 siRNA abrogated the curcumin-induced HSC senescence in vitro. Meanwhile, curcumin disruption of P53 leading to increased senescence of activated HSCs was further verified in vivo. Further studies indicated that curcumin promoted the expression of P53 through a PPARγ activation-dependent mechanism. Moreover, promoting PPARγ transactivating activity by a PPARγ agonist 15d-PGJ2 markedly enhanced curcumin induction of senescence of activated HSCs. However, the PPARγ antagonist PD68235 eliminated curcumin induction of HSC senescence. Taken together, our results provided a novel insight into the mechanisms underlying curcumin inhibition of HSC activation through inducing senescence.
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spelling pubmed-48556712016-05-10 Activation of PPARγ/P53 signaling is required for curcumin to induce hepatic stellate cell senescence Jin, H Lian, N Zhang, F Chen, L Chen, Q Lu, C Bian, M Shao, J Wu, L Zheng, S Cell Death Dis Original Article Activation of quiescent hepatic stellate cells (HSCs) is the major event in hepatic fibrogenesis, along with enhancement of cell proliferation and overproduction of extracellular matrix. Although inhibition of cell proliferation and induction of apoptosis are potential strategies to block the activation of HSCs, a better understanding of the senescence of activated HSCs can provide a new therapeutic strategy for prevention and treatment of liver fibrosis. The antioxidant curcumin, a phytochemical from turmeric, has been shown to suppress HSC activation in vitro and in vivo. The current work was aimed to evaluate the effect of curcumin on senescence of activated HSCs and to elucidate the underlying mechanisms. In this study, curcumin promoted the expression of senescence marker Hmga1 in rat fibrotic liver. In addition, curcumin increased the number of senescence-associated β-galactosidase-positive HSCs in vitro. At the same time, curcumin induced HSC senescence by elevating the expression of senescence markers P16, P21 and Hmga1, concomitant with reduced abundance of HSC activation markers α-smooth muscle actin and α1(I)-procollagen in cultured HSCs. Moreover, curcumin affected the cell cycle and telomerase activity. We further demonstrated that P53 pharmacological inhibitor pifithrin-α (PFT-α) or transfection with P53 siRNA abrogated the curcumin-induced HSC senescence in vitro. Meanwhile, curcumin disruption of P53 leading to increased senescence of activated HSCs was further verified in vivo. Further studies indicated that curcumin promoted the expression of P53 through a PPARγ activation-dependent mechanism. Moreover, promoting PPARγ transactivating activity by a PPARγ agonist 15d-PGJ2 markedly enhanced curcumin induction of senescence of activated HSCs. However, the PPARγ antagonist PD68235 eliminated curcumin induction of HSC senescence. Taken together, our results provided a novel insight into the mechanisms underlying curcumin inhibition of HSC activation through inducing senescence. Nature Publishing Group 2016-04 2016-04-14 /pmc/articles/PMC4855671/ /pubmed/27077805 http://dx.doi.org/10.1038/cddis.2016.92 Text en Copyright © 2016 Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Original Article
Jin, H
Lian, N
Zhang, F
Chen, L
Chen, Q
Lu, C
Bian, M
Shao, J
Wu, L
Zheng, S
Activation of PPARγ/P53 signaling is required for curcumin to induce hepatic stellate cell senescence
title Activation of PPARγ/P53 signaling is required for curcumin to induce hepatic stellate cell senescence
title_full Activation of PPARγ/P53 signaling is required for curcumin to induce hepatic stellate cell senescence
title_fullStr Activation of PPARγ/P53 signaling is required for curcumin to induce hepatic stellate cell senescence
title_full_unstemmed Activation of PPARγ/P53 signaling is required for curcumin to induce hepatic stellate cell senescence
title_short Activation of PPARγ/P53 signaling is required for curcumin to induce hepatic stellate cell senescence
title_sort activation of pparγ/p53 signaling is required for curcumin to induce hepatic stellate cell senescence
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4855671/
https://www.ncbi.nlm.nih.gov/pubmed/27077805
http://dx.doi.org/10.1038/cddis.2016.92
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