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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...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2022
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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 |
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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 |
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