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Transcriptional Regulation of the Angptl8 Gene by Hepatocyte Nuclear Factor-1 in the Murine Liver
Brief refeeding times (~60 min) enhanced hepatic Angptl8 expression in fasted mice. We cloned the mouse Angptl8 promoter region to characterise this rapid refeeding-induced increase in hepatic Angptl8 expression. Deletion of the −309/−60 promoter region significantly attenuated basal promoter activi...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305314/ https://www.ncbi.nlm.nih.gov/pubmed/32561878 http://dx.doi.org/10.1038/s41598-020-66570-0 |
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author | Watanabe, Takuya Ozawa, Atsushi Masuda, Shinnosuke Yoshino, Satoshi Ishida, Emi Kondo, Yuri Matsumoto, Shunichi Katano-Toki, Akiko Horiguchi, Kazuhiko Nakajima, Yasuyo Yamada, Eijiro Tomaru, Takuya Saito, Tsugumichi Ishii, Sumiyasu Shibusawa, Nobuyuki Okada, Shuichi Satoh, Tetsurou Yamada, Masanobu |
author_facet | Watanabe, Takuya Ozawa, Atsushi Masuda, Shinnosuke Yoshino, Satoshi Ishida, Emi Kondo, Yuri Matsumoto, Shunichi Katano-Toki, Akiko Horiguchi, Kazuhiko Nakajima, Yasuyo Yamada, Eijiro Tomaru, Takuya Saito, Tsugumichi Ishii, Sumiyasu Shibusawa, Nobuyuki Okada, Shuichi Satoh, Tetsurou Yamada, Masanobu |
author_sort | Watanabe, Takuya |
collection | PubMed |
description | Brief refeeding times (~60 min) enhanced hepatic Angptl8 expression in fasted mice. We cloned the mouse Angptl8 promoter region to characterise this rapid refeeding-induced increase in hepatic Angptl8 expression. Deletion of the −309/−60 promoter region significantly attenuated basal promoter activity in hepatocytes. A computational motif search revealed a potential binding motif for hepatocyte nuclear factor 1α/1β (HNF-1α/β) at −84/−68 bp of the promoter. Mutation of the HNF-1 binding site significantly decreased the promoter activity in hepatocytes, and the promoter carrying the mutated HNF-1 site was not transactivated by co-transfection of HNF-1 in a non-hepatic cell line. Silencing Hnf-1 in hepatoma cells and mouse primary hepatocytes reduced Angptl8 protein levels. Electrophoretic mobility-shift assays confirmed direct binding of Hnf-1 to its Angptl8 promoter binding motif. Hnf-1α expression levels increased after short-term refeeding, paralleling the enhanced in vivo expression of the Angptl8 protein. Chromatin immunoprecipitation (ChIP) confirmed the recruitment of endogenous Hnf-1 to the Angptl8 promoter region. Insulin-treated primary hepatocytes showed increased expression of Angptl8 protein, but knockdown of Hnf-1 completely abolished this enhancement. HNF-1 appears to play essential roles in the rapid refeeding-induced increases in Angptl8 expression. HNF-1α may therefore represent a primary medical target for ANGPTL8-related metabolic abnormalities. The study revealed the transcriptional regulation of the mouse hepatic Angptl8 gene by HNF-1. |
format | Online Article Text |
id | pubmed-7305314 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-73053142020-06-23 Transcriptional Regulation of the Angptl8 Gene by Hepatocyte Nuclear Factor-1 in the Murine Liver Watanabe, Takuya Ozawa, Atsushi Masuda, Shinnosuke Yoshino, Satoshi Ishida, Emi Kondo, Yuri Matsumoto, Shunichi Katano-Toki, Akiko Horiguchi, Kazuhiko Nakajima, Yasuyo Yamada, Eijiro Tomaru, Takuya Saito, Tsugumichi Ishii, Sumiyasu Shibusawa, Nobuyuki Okada, Shuichi Satoh, Tetsurou Yamada, Masanobu Sci Rep Article Brief refeeding times (~60 min) enhanced hepatic Angptl8 expression in fasted mice. We cloned the mouse Angptl8 promoter region to characterise this rapid refeeding-induced increase in hepatic Angptl8 expression. Deletion of the −309/−60 promoter region significantly attenuated basal promoter activity in hepatocytes. A computational motif search revealed a potential binding motif for hepatocyte nuclear factor 1α/1β (HNF-1α/β) at −84/−68 bp of the promoter. Mutation of the HNF-1 binding site significantly decreased the promoter activity in hepatocytes, and the promoter carrying the mutated HNF-1 site was not transactivated by co-transfection of HNF-1 in a non-hepatic cell line. Silencing Hnf-1 in hepatoma cells and mouse primary hepatocytes reduced Angptl8 protein levels. Electrophoretic mobility-shift assays confirmed direct binding of Hnf-1 to its Angptl8 promoter binding motif. Hnf-1α expression levels increased after short-term refeeding, paralleling the enhanced in vivo expression of the Angptl8 protein. Chromatin immunoprecipitation (ChIP) confirmed the recruitment of endogenous Hnf-1 to the Angptl8 promoter region. Insulin-treated primary hepatocytes showed increased expression of Angptl8 protein, but knockdown of Hnf-1 completely abolished this enhancement. HNF-1 appears to play essential roles in the rapid refeeding-induced increases in Angptl8 expression. HNF-1α may therefore represent a primary medical target for ANGPTL8-related metabolic abnormalities. The study revealed the transcriptional regulation of the mouse hepatic Angptl8 gene by HNF-1. Nature Publishing Group UK 2020-06-19 /pmc/articles/PMC7305314/ /pubmed/32561878 http://dx.doi.org/10.1038/s41598-020-66570-0 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Watanabe, Takuya Ozawa, Atsushi Masuda, Shinnosuke Yoshino, Satoshi Ishida, Emi Kondo, Yuri Matsumoto, Shunichi Katano-Toki, Akiko Horiguchi, Kazuhiko Nakajima, Yasuyo Yamada, Eijiro Tomaru, Takuya Saito, Tsugumichi Ishii, Sumiyasu Shibusawa, Nobuyuki Okada, Shuichi Satoh, Tetsurou Yamada, Masanobu Transcriptional Regulation of the Angptl8 Gene by Hepatocyte Nuclear Factor-1 in the Murine Liver |
title | Transcriptional Regulation of the Angptl8 Gene by Hepatocyte Nuclear Factor-1 in the Murine Liver |
title_full | Transcriptional Regulation of the Angptl8 Gene by Hepatocyte Nuclear Factor-1 in the Murine Liver |
title_fullStr | Transcriptional Regulation of the Angptl8 Gene by Hepatocyte Nuclear Factor-1 in the Murine Liver |
title_full_unstemmed | Transcriptional Regulation of the Angptl8 Gene by Hepatocyte Nuclear Factor-1 in the Murine Liver |
title_short | Transcriptional Regulation of the Angptl8 Gene by Hepatocyte Nuclear Factor-1 in the Murine Liver |
title_sort | transcriptional regulation of the angptl8 gene by hepatocyte nuclear factor-1 in the murine liver |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305314/ https://www.ncbi.nlm.nih.gov/pubmed/32561878 http://dx.doi.org/10.1038/s41598-020-66570-0 |
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