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Short-term tamoxifen administration improves hepatic steatosis and glucose intolerance through JNK/MAPK in mice

Nonalcoholic fatty liver disease (NAFLD) which is a leading cause of chronic liver diseases lacks effective treatment. Tamoxifen has been proven to be the first-line chemotherapy for several solid tumors in clinics, however, its therapeutic role in NAFLD has never been elucidated before. In vitro ex...

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Autores principales: Fang, Zhiqiang, Xu, Hao, Duan, Juanli, Ruan, Bai, Liu, Jingjing, Song, Ping, Ding, Jian, Xu, Chen, Li, Zhiwen, Dou, Kefeng, Wang, Lin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9981902/
https://www.ncbi.nlm.nih.gov/pubmed/36864030
http://dx.doi.org/10.1038/s41392-022-01299-y
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author Fang, Zhiqiang
Xu, Hao
Duan, Juanli
Ruan, Bai
Liu, Jingjing
Song, Ping
Ding, Jian
Xu, Chen
Li, Zhiwen
Dou, Kefeng
Wang, Lin
author_facet Fang, Zhiqiang
Xu, Hao
Duan, Juanli
Ruan, Bai
Liu, Jingjing
Song, Ping
Ding, Jian
Xu, Chen
Li, Zhiwen
Dou, Kefeng
Wang, Lin
author_sort Fang, Zhiqiang
collection PubMed
description Nonalcoholic fatty liver disease (NAFLD) which is a leading cause of chronic liver diseases lacks effective treatment. Tamoxifen has been proven to be the first-line chemotherapy for several solid tumors in clinics, however, its therapeutic role in NAFLD has never been elucidated before. In vitro experiments, tamoxifen protected hepatocytes against sodium palmitate-induced lipotoxicity. In male and female mice fed with normal diets, continuous tamoxifen administration inhibited lipid accumulation in liver, and improved glucose and insulin intolerance. Short-term tamoxifen administration largely improved hepatic steatosis and insulin resistance, however, the phenotypes manifesting inflammation and fibrosis remained unchanged in abovementioned models. In addition, mRNA expressions of genes related to lipogenesis, inflammation, and fibrosis were downregulated by tamoxifen treatment. Moreover, the therapeutic effect of tamoxifen on NAFLD was not gender or ER dependent, as male and female mice with metabolic disorders shared no difference in response to tamoxifen and ER antagonist (fulvestrant) did not abolish its therapeutic effect as well. Mechanistically, RNA sequence of hepatocytes isolated from fatty liver revealed that JNK/MAPK signaling pathway was inactivated by tamoxifen. Pharmacological JNK activator (anisomycin) partially deprived the therapeutic role of tamoxifen in treating hepatic steatosis, proving tamoxifen improved NAFLD in a JNK/MAPK signaling-dependent manner.
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spelling pubmed-99819022023-03-04 Short-term tamoxifen administration improves hepatic steatosis and glucose intolerance through JNK/MAPK in mice Fang, Zhiqiang Xu, Hao Duan, Juanli Ruan, Bai Liu, Jingjing Song, Ping Ding, Jian Xu, Chen Li, Zhiwen Dou, Kefeng Wang, Lin Signal Transduct Target Ther Article Nonalcoholic fatty liver disease (NAFLD) which is a leading cause of chronic liver diseases lacks effective treatment. Tamoxifen has been proven to be the first-line chemotherapy for several solid tumors in clinics, however, its therapeutic role in NAFLD has never been elucidated before. In vitro experiments, tamoxifen protected hepatocytes against sodium palmitate-induced lipotoxicity. In male and female mice fed with normal diets, continuous tamoxifen administration inhibited lipid accumulation in liver, and improved glucose and insulin intolerance. Short-term tamoxifen administration largely improved hepatic steatosis and insulin resistance, however, the phenotypes manifesting inflammation and fibrosis remained unchanged in abovementioned models. In addition, mRNA expressions of genes related to lipogenesis, inflammation, and fibrosis were downregulated by tamoxifen treatment. Moreover, the therapeutic effect of tamoxifen on NAFLD was not gender or ER dependent, as male and female mice with metabolic disorders shared no difference in response to tamoxifen and ER antagonist (fulvestrant) did not abolish its therapeutic effect as well. Mechanistically, RNA sequence of hepatocytes isolated from fatty liver revealed that JNK/MAPK signaling pathway was inactivated by tamoxifen. Pharmacological JNK activator (anisomycin) partially deprived the therapeutic role of tamoxifen in treating hepatic steatosis, proving tamoxifen improved NAFLD in a JNK/MAPK signaling-dependent manner. Nature Publishing Group UK 2023-03-03 /pmc/articles/PMC9981902/ /pubmed/36864030 http://dx.doi.org/10.1038/s41392-022-01299-y Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Fang, Zhiqiang
Xu, Hao
Duan, Juanli
Ruan, Bai
Liu, Jingjing
Song, Ping
Ding, Jian
Xu, Chen
Li, Zhiwen
Dou, Kefeng
Wang, Lin
Short-term tamoxifen administration improves hepatic steatosis and glucose intolerance through JNK/MAPK in mice
title Short-term tamoxifen administration improves hepatic steatosis and glucose intolerance through JNK/MAPK in mice
title_full Short-term tamoxifen administration improves hepatic steatosis and glucose intolerance through JNK/MAPK in mice
title_fullStr Short-term tamoxifen administration improves hepatic steatosis and glucose intolerance through JNK/MAPK in mice
title_full_unstemmed Short-term tamoxifen administration improves hepatic steatosis and glucose intolerance through JNK/MAPK in mice
title_short Short-term tamoxifen administration improves hepatic steatosis and glucose intolerance through JNK/MAPK in mice
title_sort short-term tamoxifen administration improves hepatic steatosis and glucose intolerance through jnk/mapk in mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9981902/
https://www.ncbi.nlm.nih.gov/pubmed/36864030
http://dx.doi.org/10.1038/s41392-022-01299-y
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