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CDKN2a/p16 Antagonizes Hepatic Stellate Cell Activation and Liver Fibrosis by Modulating ROS Levels

The lipid-storage hepatic stellate cells (HSC) play as pivotal role in liver fibrosis being able to trans-differentiate into myofibroblasts in response to various pro-fibrogenic stimuli. In the present study we investigated the role of CDKN2a/p16, a negative regulator of cell cycling, in HSC activat...

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Autores principales: Lv, Fangqiao, Li, Nan, Kong, Ming, Wu, Jun, Fan, Zhiwen, Miao, Dengshun, Xu, Yong, Ye, Qing, Wang, Yutong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7105638/
https://www.ncbi.nlm.nih.gov/pubmed/32266258
http://dx.doi.org/10.3389/fcell.2020.00176
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author Lv, Fangqiao
Li, Nan
Kong, Ming
Wu, Jun
Fan, Zhiwen
Miao, Dengshun
Xu, Yong
Ye, Qing
Wang, Yutong
author_facet Lv, Fangqiao
Li, Nan
Kong, Ming
Wu, Jun
Fan, Zhiwen
Miao, Dengshun
Xu, Yong
Ye, Qing
Wang, Yutong
author_sort Lv, Fangqiao
collection PubMed
description The lipid-storage hepatic stellate cells (HSC) play as pivotal role in liver fibrosis being able to trans-differentiate into myofibroblasts in response to various pro-fibrogenic stimuli. In the present study we investigated the role of CDKN2a/p16, a negative regulator of cell cycling, in HSC activation and the underlying mechanism. Levels of p16 were significantly down-regulated in activated HSCs isolated from mice induced to develop liver fibrosis compared to quiescent HSCs isolated from the control mice ex vivo. There was a similar decrease in p16 expression in cultured HSCs undergoing spontaneous activation or exposed to TGF-β treatment in vitro. More important, p16 down-regulation was observed to correlate with cirrhosis in humans. In a classic model of carbon tetrachloride (CCl(4)) induced liver fibrosis, fibrogenesis was far more extensive in mice with p16 deficiency (KO) than the wild type (WT) littermates. Depletion of p16 in cultured HSCs promoted the synthesis of extracellular matrix (ECM) proteins. Mechanistically, p16 deficiency accelerated reactive oxygen species (ROS) generation in HSCs likely through the p38 MAPK signaling. P38 inhibition or ROS cleansing attenuated ECM production in p16 deficient HSCs. Taken together, our data unveil a previously unappreciated role for p16 in the regulation of HSC activation. Screening for small-molecule compounds that can boost p16 activity may yield novel therapeutic strategies against liver fibrosis.
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spelling pubmed-71056382020-04-07 CDKN2a/p16 Antagonizes Hepatic Stellate Cell Activation and Liver Fibrosis by Modulating ROS Levels Lv, Fangqiao Li, Nan Kong, Ming Wu, Jun Fan, Zhiwen Miao, Dengshun Xu, Yong Ye, Qing Wang, Yutong Front Cell Dev Biol Cell and Developmental Biology The lipid-storage hepatic stellate cells (HSC) play as pivotal role in liver fibrosis being able to trans-differentiate into myofibroblasts in response to various pro-fibrogenic stimuli. In the present study we investigated the role of CDKN2a/p16, a negative regulator of cell cycling, in HSC activation and the underlying mechanism. Levels of p16 were significantly down-regulated in activated HSCs isolated from mice induced to develop liver fibrosis compared to quiescent HSCs isolated from the control mice ex vivo. There was a similar decrease in p16 expression in cultured HSCs undergoing spontaneous activation or exposed to TGF-β treatment in vitro. More important, p16 down-regulation was observed to correlate with cirrhosis in humans. In a classic model of carbon tetrachloride (CCl(4)) induced liver fibrosis, fibrogenesis was far more extensive in mice with p16 deficiency (KO) than the wild type (WT) littermates. Depletion of p16 in cultured HSCs promoted the synthesis of extracellular matrix (ECM) proteins. Mechanistically, p16 deficiency accelerated reactive oxygen species (ROS) generation in HSCs likely through the p38 MAPK signaling. P38 inhibition or ROS cleansing attenuated ECM production in p16 deficient HSCs. Taken together, our data unveil a previously unappreciated role for p16 in the regulation of HSC activation. Screening for small-molecule compounds that can boost p16 activity may yield novel therapeutic strategies against liver fibrosis. Frontiers Media S.A. 2020-03-24 /pmc/articles/PMC7105638/ /pubmed/32266258 http://dx.doi.org/10.3389/fcell.2020.00176 Text en Copyright © 2020 Lv, Li, Kong, Wu, Fan, Miao, Xu, Ye and Wang. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Lv, Fangqiao
Li, Nan
Kong, Ming
Wu, Jun
Fan, Zhiwen
Miao, Dengshun
Xu, Yong
Ye, Qing
Wang, Yutong
CDKN2a/p16 Antagonizes Hepatic Stellate Cell Activation and Liver Fibrosis by Modulating ROS Levels
title CDKN2a/p16 Antagonizes Hepatic Stellate Cell Activation and Liver Fibrosis by Modulating ROS Levels
title_full CDKN2a/p16 Antagonizes Hepatic Stellate Cell Activation and Liver Fibrosis by Modulating ROS Levels
title_fullStr CDKN2a/p16 Antagonizes Hepatic Stellate Cell Activation and Liver Fibrosis by Modulating ROS Levels
title_full_unstemmed CDKN2a/p16 Antagonizes Hepatic Stellate Cell Activation and Liver Fibrosis by Modulating ROS Levels
title_short CDKN2a/p16 Antagonizes Hepatic Stellate Cell Activation and Liver Fibrosis by Modulating ROS Levels
title_sort cdkn2a/p16 antagonizes hepatic stellate cell activation and liver fibrosis by modulating ros levels
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7105638/
https://www.ncbi.nlm.nih.gov/pubmed/32266258
http://dx.doi.org/10.3389/fcell.2020.00176
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