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Effects of 2-Methoxyestradiol, a Main Metabolite of Estradiol on Hepatic ABCA1 Expression in HepG2 Cells

ATP-binding cassette transporter A1 (ABCA1) is a key regulator of lipid efflux, and the absence of ABCA1 induces hepatic lipid accumulation, which is one of the major causes of fatty liver. 2-Methoxyestradiol (2-ME(2)) has been demonstrated to protect against fatty liver. In this study, we investiga...

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Autores principales: Ibata, Tomohiro, Lyu, Jingya, Imachi, Hitomi, Fukunaga, Kensaku, Sato, Seisuke, Kobayashi, Toshihiro, Saheki, Takanobu, Yoshimura, Takafumi, Murao, Koji
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8779252/
https://www.ncbi.nlm.nih.gov/pubmed/35057469
http://dx.doi.org/10.3390/nu14020288
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author Ibata, Tomohiro
Lyu, Jingya
Imachi, Hitomi
Fukunaga, Kensaku
Sato, Seisuke
Kobayashi, Toshihiro
Saheki, Takanobu
Yoshimura, Takafumi
Murao, Koji
author_facet Ibata, Tomohiro
Lyu, Jingya
Imachi, Hitomi
Fukunaga, Kensaku
Sato, Seisuke
Kobayashi, Toshihiro
Saheki, Takanobu
Yoshimura, Takafumi
Murao, Koji
author_sort Ibata, Tomohiro
collection PubMed
description ATP-binding cassette transporter A1 (ABCA1) is a key regulator of lipid efflux, and the absence of ABCA1 induces hepatic lipid accumulation, which is one of the major causes of fatty liver. 2-Methoxyestradiol (2-ME(2)) has been demonstrated to protect against fatty liver. In this study, we investigated the effects of 2-ME(2) on the hepatic lipid content and ABCA1 expression. We found that 2-ME(2) dose-dependently increased ABCA1 expression, and therefore, the lipid content was significantly decreased in HepG2 cells. 2-ME(2) enhanced the ABCA1 promoter activity; however, this effect was reduced after the inhibition of the PI3K pathway. The overexpression of Akt or p110 induced ABCA1 promoter activity, while dominant-negative Akt diminished the ability of 2-ME(2) on ABCA1 promoter activity. Further, 2-ME(2) stimulated the rapid phosphorylation of Akt and FoxO1 and reduced the nuclear accumulation of FoxO1. Chromatin immunoprecipitation confirmed that FoxO1 bonded to the ABCA1 promoter region. The binding was reduced by 2-ME(2), which facilitated ABCA1 gene transcription. Furthermore, mutating FoxO1-binding sites in the ABCA1 promoter region or treatment with FoxO1-specific siRNA disrupted the effect of 2-ME(2) on ABCA1 expression. All of our results demonstrated that 2-ME(2) might upregulate ABCA1 expression via the PI3K/Akt/FoxO1 pathway, which thus reduces the lipid content in hepatocytes.
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spelling pubmed-87792522022-01-22 Effects of 2-Methoxyestradiol, a Main Metabolite of Estradiol on Hepatic ABCA1 Expression in HepG2 Cells Ibata, Tomohiro Lyu, Jingya Imachi, Hitomi Fukunaga, Kensaku Sato, Seisuke Kobayashi, Toshihiro Saheki, Takanobu Yoshimura, Takafumi Murao, Koji Nutrients Article ATP-binding cassette transporter A1 (ABCA1) is a key regulator of lipid efflux, and the absence of ABCA1 induces hepatic lipid accumulation, which is one of the major causes of fatty liver. 2-Methoxyestradiol (2-ME(2)) has been demonstrated to protect against fatty liver. In this study, we investigated the effects of 2-ME(2) on the hepatic lipid content and ABCA1 expression. We found that 2-ME(2) dose-dependently increased ABCA1 expression, and therefore, the lipid content was significantly decreased in HepG2 cells. 2-ME(2) enhanced the ABCA1 promoter activity; however, this effect was reduced after the inhibition of the PI3K pathway. The overexpression of Akt or p110 induced ABCA1 promoter activity, while dominant-negative Akt diminished the ability of 2-ME(2) on ABCA1 promoter activity. Further, 2-ME(2) stimulated the rapid phosphorylation of Akt and FoxO1 and reduced the nuclear accumulation of FoxO1. Chromatin immunoprecipitation confirmed that FoxO1 bonded to the ABCA1 promoter region. The binding was reduced by 2-ME(2), which facilitated ABCA1 gene transcription. Furthermore, mutating FoxO1-binding sites in the ABCA1 promoter region or treatment with FoxO1-specific siRNA disrupted the effect of 2-ME(2) on ABCA1 expression. All of our results demonstrated that 2-ME(2) might upregulate ABCA1 expression via the PI3K/Akt/FoxO1 pathway, which thus reduces the lipid content in hepatocytes. MDPI 2022-01-11 /pmc/articles/PMC8779252/ /pubmed/35057469 http://dx.doi.org/10.3390/nu14020288 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ibata, Tomohiro
Lyu, Jingya
Imachi, Hitomi
Fukunaga, Kensaku
Sato, Seisuke
Kobayashi, Toshihiro
Saheki, Takanobu
Yoshimura, Takafumi
Murao, Koji
Effects of 2-Methoxyestradiol, a Main Metabolite of Estradiol on Hepatic ABCA1 Expression in HepG2 Cells
title Effects of 2-Methoxyestradiol, a Main Metabolite of Estradiol on Hepatic ABCA1 Expression in HepG2 Cells
title_full Effects of 2-Methoxyestradiol, a Main Metabolite of Estradiol on Hepatic ABCA1 Expression in HepG2 Cells
title_fullStr Effects of 2-Methoxyestradiol, a Main Metabolite of Estradiol on Hepatic ABCA1 Expression in HepG2 Cells
title_full_unstemmed Effects of 2-Methoxyestradiol, a Main Metabolite of Estradiol on Hepatic ABCA1 Expression in HepG2 Cells
title_short Effects of 2-Methoxyestradiol, a Main Metabolite of Estradiol on Hepatic ABCA1 Expression in HepG2 Cells
title_sort effects of 2-methoxyestradiol, a main metabolite of estradiol on hepatic abca1 expression in hepg2 cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8779252/
https://www.ncbi.nlm.nih.gov/pubmed/35057469
http://dx.doi.org/10.3390/nu14020288
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