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Bone morphogenetic protein 4 alleviates nonalcoholic steatohepatitis by inhibiting hepatic ferroptosis

Nonalcoholic steatohepatitis (NASH) is a state of simple steatosis that progresses to inflammation and liver injury accompanied by ferroptosis. Bone morphogenetic protein 4 (BMP4) plays an important role in adipogenesis and differentiation, as well as in hepatic steatosis and iron regulation. Howeve...

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Autores principales: Wang, Xingchun, Ma, Bingwei, Wen, Xin, You, Hui, Sheng, Chunjun, Bu, Le, Qu, Shen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9046379/
https://www.ncbi.nlm.nih.gov/pubmed/35477568
http://dx.doi.org/10.1038/s41420-022-01011-7
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author Wang, Xingchun
Ma, Bingwei
Wen, Xin
You, Hui
Sheng, Chunjun
Bu, Le
Qu, Shen
author_facet Wang, Xingchun
Ma, Bingwei
Wen, Xin
You, Hui
Sheng, Chunjun
Bu, Le
Qu, Shen
author_sort Wang, Xingchun
collection PubMed
description Nonalcoholic steatohepatitis (NASH) is a state of simple steatosis that progresses to inflammation and liver injury accompanied by ferroptosis. Bone morphogenetic protein 4 (BMP4) plays an important role in adipogenesis and differentiation, as well as in hepatic steatosis and iron regulation. However, the direct impact of BMP4 on NASH remains unclear. In this study, our aim was to investigate the effect of BMP4 on NASH and its underlying mechanism. We first explored BMP4 expression in vivo in mice and patients and in vitro in HepG2 and LO2 cell lines, and then, determined whether ferroptosis occurs in NASH. Further overexpression or inhibition of BMP4 was induced to observe the effect of BMP4 on liver ferroptosis in NASH. BMP4 expression was upregulated in patients and mice with nonalcoholic fatty liver disease, and free fatty acid (FFA)-induced HepG2 and LO2 cell lines. We observed ferroptosis in high-fat diet and high-fructose diet-fed mice and FFA-induced HepG2 and LO2 cell lines. BMP4 overexpressing plasmid was constructed and the HepG2 and LO2 cells were transfected with lentivirus (oe-BMP4), or treated with exogenously added recombinant human BMP4 or BMP antagonist noggin. BMP4 suppressed the markers of hepatic steatosis, liver inflammation, and liver injury. Upregulated BMP4 expression in HepG2 and LO2 cells reduced reactive oxygen species and malondialdehyde content and relieved ferroptosis. Mechanistically, BMP4 overexpression in hepatocytes upregulated the mRNA and protein levels of glutathione peroxidase 4 (GPX4), a central regulator of ferroptosis, while exogenous inhibition of BMP4 by noggin decreased their levels. Immunoprecipitation assays demonstrated a physical interaction between BMP4 and GPX4 in HepG2 and LO2 cells, and confocal imaging confirmed colocalization of BMP4 and GPX4. Consistently, BMP4 overexpression plays an important role in NASH by increasing GPX4 expression, therefore decreasing hepatic ferroptosis. This study proposes BMP4 as a therapeutic target for preventing steatohepatitis.
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spelling pubmed-90463792022-04-29 Bone morphogenetic protein 4 alleviates nonalcoholic steatohepatitis by inhibiting hepatic ferroptosis Wang, Xingchun Ma, Bingwei Wen, Xin You, Hui Sheng, Chunjun Bu, Le Qu, Shen Cell Death Discov Article Nonalcoholic steatohepatitis (NASH) is a state of simple steatosis that progresses to inflammation and liver injury accompanied by ferroptosis. Bone morphogenetic protein 4 (BMP4) plays an important role in adipogenesis and differentiation, as well as in hepatic steatosis and iron regulation. However, the direct impact of BMP4 on NASH remains unclear. In this study, our aim was to investigate the effect of BMP4 on NASH and its underlying mechanism. We first explored BMP4 expression in vivo in mice and patients and in vitro in HepG2 and LO2 cell lines, and then, determined whether ferroptosis occurs in NASH. Further overexpression or inhibition of BMP4 was induced to observe the effect of BMP4 on liver ferroptosis in NASH. BMP4 expression was upregulated in patients and mice with nonalcoholic fatty liver disease, and free fatty acid (FFA)-induced HepG2 and LO2 cell lines. We observed ferroptosis in high-fat diet and high-fructose diet-fed mice and FFA-induced HepG2 and LO2 cell lines. BMP4 overexpressing plasmid was constructed and the HepG2 and LO2 cells were transfected with lentivirus (oe-BMP4), or treated with exogenously added recombinant human BMP4 or BMP antagonist noggin. BMP4 suppressed the markers of hepatic steatosis, liver inflammation, and liver injury. Upregulated BMP4 expression in HepG2 and LO2 cells reduced reactive oxygen species and malondialdehyde content and relieved ferroptosis. Mechanistically, BMP4 overexpression in hepatocytes upregulated the mRNA and protein levels of glutathione peroxidase 4 (GPX4), a central regulator of ferroptosis, while exogenous inhibition of BMP4 by noggin decreased their levels. Immunoprecipitation assays demonstrated a physical interaction between BMP4 and GPX4 in HepG2 and LO2 cells, and confocal imaging confirmed colocalization of BMP4 and GPX4. Consistently, BMP4 overexpression plays an important role in NASH by increasing GPX4 expression, therefore decreasing hepatic ferroptosis. This study proposes BMP4 as a therapeutic target for preventing steatohepatitis. Nature Publishing Group UK 2022-04-27 /pmc/articles/PMC9046379/ /pubmed/35477568 http://dx.doi.org/10.1038/s41420-022-01011-7 Text en © The Author(s) 2022, corrected publication 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
Wang, Xingchun
Ma, Bingwei
Wen, Xin
You, Hui
Sheng, Chunjun
Bu, Le
Qu, Shen
Bone morphogenetic protein 4 alleviates nonalcoholic steatohepatitis by inhibiting hepatic ferroptosis
title Bone morphogenetic protein 4 alleviates nonalcoholic steatohepatitis by inhibiting hepatic ferroptosis
title_full Bone morphogenetic protein 4 alleviates nonalcoholic steatohepatitis by inhibiting hepatic ferroptosis
title_fullStr Bone morphogenetic protein 4 alleviates nonalcoholic steatohepatitis by inhibiting hepatic ferroptosis
title_full_unstemmed Bone morphogenetic protein 4 alleviates nonalcoholic steatohepatitis by inhibiting hepatic ferroptosis
title_short Bone morphogenetic protein 4 alleviates nonalcoholic steatohepatitis by inhibiting hepatic ferroptosis
title_sort bone morphogenetic protein 4 alleviates nonalcoholic steatohepatitis by inhibiting hepatic ferroptosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9046379/
https://www.ncbi.nlm.nih.gov/pubmed/35477568
http://dx.doi.org/10.1038/s41420-022-01011-7
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