Cargando…

Gene repression through epigenetic modulation by PPARA enhances hepatocellular proliferation

Peroxisome proliferator-activated receptor α (PPARA) is a key mediator of lipid metabolism and inflammation. Activation of PPARA in rodents causes hepatocyte proliferation, but the underlying mechanism is poorly understood. This study focused on genes repressed by PPARA and analyzed the mechanism by...

Descripción completa

Detalles Bibliográficos
Autores principales: Aibara, Daisuke, Takahashi, Shogo, Yagai, Tomoki, Kim, Donghwan, Brocker, Chad N., Levi, Moshe, Matsusue, Kimihiko, Gonzalez, Frank J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9036120/
https://www.ncbi.nlm.nih.gov/pubmed/35479397
http://dx.doi.org/10.1016/j.isci.2022.104196
_version_ 1784693454021853184
author Aibara, Daisuke
Takahashi, Shogo
Yagai, Tomoki
Kim, Donghwan
Brocker, Chad N.
Levi, Moshe
Matsusue, Kimihiko
Gonzalez, Frank J.
author_facet Aibara, Daisuke
Takahashi, Shogo
Yagai, Tomoki
Kim, Donghwan
Brocker, Chad N.
Levi, Moshe
Matsusue, Kimihiko
Gonzalez, Frank J.
author_sort Aibara, Daisuke
collection PubMed
description Peroxisome proliferator-activated receptor α (PPARA) is a key mediator of lipid metabolism and inflammation. Activation of PPARA in rodents causes hepatocyte proliferation, but the underlying mechanism is poorly understood. This study focused on genes repressed by PPARA and analyzed the mechanism by which PPARA promotes hepatocyte proliferation in mice. Activation of PPARA by agonist treatment was autoregulated, and induced expression of the epigenetic regulator UHRF1 via activation of the newly described PPARA target gene E2f8, which, in turn, regulates Uhrf1. UHRF1 strongly repressed the expression of CDH1 via methylation of the Cdh1 promoter marked with H3K9me3. Repression of CDH1 by PPARA activation was reversed by PPARA deficiency or knockdown of E2F8 or UHRF1. Furthermore, a forced expression of CDH1 inhibited expression of the Wnt signaling target genes such as Myc after PPARA activation, and suppressed hepatocyte hyperproliferation. These results demonstrate that the PPARA-E2F8-UHRF1-CDH1 axis causes epigenetic regulation of hepatocyte proliferation.
format Online
Article
Text
id pubmed-9036120
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Elsevier
record_format MEDLINE/PubMed
spelling pubmed-90361202022-04-26 Gene repression through epigenetic modulation by PPARA enhances hepatocellular proliferation Aibara, Daisuke Takahashi, Shogo Yagai, Tomoki Kim, Donghwan Brocker, Chad N. Levi, Moshe Matsusue, Kimihiko Gonzalez, Frank J. iScience Article Peroxisome proliferator-activated receptor α (PPARA) is a key mediator of lipid metabolism and inflammation. Activation of PPARA in rodents causes hepatocyte proliferation, but the underlying mechanism is poorly understood. This study focused on genes repressed by PPARA and analyzed the mechanism by which PPARA promotes hepatocyte proliferation in mice. Activation of PPARA by agonist treatment was autoregulated, and induced expression of the epigenetic regulator UHRF1 via activation of the newly described PPARA target gene E2f8, which, in turn, regulates Uhrf1. UHRF1 strongly repressed the expression of CDH1 via methylation of the Cdh1 promoter marked with H3K9me3. Repression of CDH1 by PPARA activation was reversed by PPARA deficiency or knockdown of E2F8 or UHRF1. Furthermore, a forced expression of CDH1 inhibited expression of the Wnt signaling target genes such as Myc after PPARA activation, and suppressed hepatocyte hyperproliferation. These results demonstrate that the PPARA-E2F8-UHRF1-CDH1 axis causes epigenetic regulation of hepatocyte proliferation. Elsevier 2022-04-04 /pmc/articles/PMC9036120/ /pubmed/35479397 http://dx.doi.org/10.1016/j.isci.2022.104196 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Aibara, Daisuke
Takahashi, Shogo
Yagai, Tomoki
Kim, Donghwan
Brocker, Chad N.
Levi, Moshe
Matsusue, Kimihiko
Gonzalez, Frank J.
Gene repression through epigenetic modulation by PPARA enhances hepatocellular proliferation
title Gene repression through epigenetic modulation by PPARA enhances hepatocellular proliferation
title_full Gene repression through epigenetic modulation by PPARA enhances hepatocellular proliferation
title_fullStr Gene repression through epigenetic modulation by PPARA enhances hepatocellular proliferation
title_full_unstemmed Gene repression through epigenetic modulation by PPARA enhances hepatocellular proliferation
title_short Gene repression through epigenetic modulation by PPARA enhances hepatocellular proliferation
title_sort gene repression through epigenetic modulation by ppara enhances hepatocellular proliferation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9036120/
https://www.ncbi.nlm.nih.gov/pubmed/35479397
http://dx.doi.org/10.1016/j.isci.2022.104196
work_keys_str_mv AT aibaradaisuke generepressionthroughepigeneticmodulationbypparaenhanceshepatocellularproliferation
AT takahashishogo generepressionthroughepigeneticmodulationbypparaenhanceshepatocellularproliferation
AT yagaitomoki generepressionthroughepigeneticmodulationbypparaenhanceshepatocellularproliferation
AT kimdonghwan generepressionthroughepigeneticmodulationbypparaenhanceshepatocellularproliferation
AT brockerchadn generepressionthroughepigeneticmodulationbypparaenhanceshepatocellularproliferation
AT levimoshe generepressionthroughepigeneticmodulationbypparaenhanceshepatocellularproliferation
AT matsusuekimihiko generepressionthroughepigeneticmodulationbypparaenhanceshepatocellularproliferation
AT gonzalezfrankj generepressionthroughepigeneticmodulationbypparaenhanceshepatocellularproliferation