Albumin inhibits the nuclear translocation of Smad3 via interleukin-1beta signaling in hepatic stellate cells

Abstract Activation of quiescent hepatic stellate cells (HSCs) to myofibroblasts plays a key role in liver fibrosis. We had previously shown that albumin and its derivative, R-III (a retinol-binding protein—albumin domain III fusion protein), inhibited HSC activation by sequestering retinoic acid (R...

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Autores principales:	Ji Hoon Park, Janghyun Kim, So-Young Choi, Boram Lee, Jung-Eun Lee, Heekyung Park, Ji Wook Moon, Sun-Hwa Park, Jae Min Lee, Hong Sik Lee, Junseo Oh
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/886a0473bd5e4724bb9ad46c21bd2971
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spelling	oai:doaj.org-article:886a0473bd5e4724bb9ad46c21bd29712021-12-02T10:44:14ZAlbumin inhibits the nuclear translocation of Smad3 via interleukin-1beta signaling in hepatic stellate cells10.1038/s41598-021-82758-42045-2322https://doaj.org/article/886a0473bd5e4724bb9ad46c21bd29712021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-82758-4https://doaj.org/toc/2045-2322Abstract Activation of quiescent hepatic stellate cells (HSCs) to myofibroblasts plays a key role in liver fibrosis. We had previously shown that albumin and its derivative, R-III (a retinol-binding protein—albumin domain III fusion protein), inhibited HSC activation by sequestering retinoic acid (RA) and that R-III administration reduced carbon tetrachloride (CCl4)-induced liver fibrosis. In this study, we aimed to elucidate the mechanism of action of albumin downstream of RA sequestration. Nuclear factor-κB p65 was evenly distributed in the cytoplasm in activated mouse HSCs, whereas albumin expression or R-III treatment (albumin/R-III) caused the nuclear translocation of p65, probably via RA sequestration, resulting in a dramatic increase in interleukin-1beta (IL-1β) expression. Albumin/R-III in turn induced the phosphorylation of Smad3 at the linker region, inhibiting its nuclear import in an IL-1β-dependent manner. Consistent with the in vitro results, the level of IL-1β mRNA expression was higher in CCl4/R-III-treated livers than in CCl4-treated livers. These findings reveal that albumin/R-III inhibits the transforming growth factor-β-Smad3 signaling as well as the retinoic acid receptor-mediated pathway, which probably contributes to the inhibition of HSC activation, and suggest that R-III may be an anti-fibrotic drug candidate.Ji Hoon ParkJanghyun KimSo-Young ChoiBoram LeeJung-Eun LeeHeekyung ParkJi Wook MoonSun-Hwa ParkJae Min LeeHong Sik LeeJunseo OhNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ji Hoon Park Janghyun Kim So-Young Choi Boram Lee Jung-Eun Lee Heekyung Park Ji Wook Moon Sun-Hwa Park Jae Min Lee Hong Sik Lee Junseo Oh Albumin inhibits the nuclear translocation of Smad3 via interleukin-1beta signaling in hepatic stellate cells
description	Abstract Activation of quiescent hepatic stellate cells (HSCs) to myofibroblasts plays a key role in liver fibrosis. We had previously shown that albumin and its derivative, R-III (a retinol-binding protein—albumin domain III fusion protein), inhibited HSC activation by sequestering retinoic acid (RA) and that R-III administration reduced carbon tetrachloride (CCl4)-induced liver fibrosis. In this study, we aimed to elucidate the mechanism of action of albumin downstream of RA sequestration. Nuclear factor-κB p65 was evenly distributed in the cytoplasm in activated mouse HSCs, whereas albumin expression or R-III treatment (albumin/R-III) caused the nuclear translocation of p65, probably via RA sequestration, resulting in a dramatic increase in interleukin-1beta (IL-1β) expression. Albumin/R-III in turn induced the phosphorylation of Smad3 at the linker region, inhibiting its nuclear import in an IL-1β-dependent manner. Consistent with the in vitro results, the level of IL-1β mRNA expression was higher in CCl4/R-III-treated livers than in CCl4-treated livers. These findings reveal that albumin/R-III inhibits the transforming growth factor-β-Smad3 signaling as well as the retinoic acid receptor-mediated pathway, which probably contributes to the inhibition of HSC activation, and suggest that R-III may be an anti-fibrotic drug candidate.
format	article
author	Ji Hoon Park Janghyun Kim So-Young Choi Boram Lee Jung-Eun Lee Heekyung Park Ji Wook Moon Sun-Hwa Park Jae Min Lee Hong Sik Lee Junseo Oh
author_facet	Ji Hoon Park Janghyun Kim So-Young Choi Boram Lee Jung-Eun Lee Heekyung Park Ji Wook Moon Sun-Hwa Park Jae Min Lee Hong Sik Lee Junseo Oh
author_sort	Ji Hoon Park
title	Albumin inhibits the nuclear translocation of Smad3 via interleukin-1beta signaling in hepatic stellate cells
title_short	Albumin inhibits the nuclear translocation of Smad3 via interleukin-1beta signaling in hepatic stellate cells
title_full	Albumin inhibits the nuclear translocation of Smad3 via interleukin-1beta signaling in hepatic stellate cells
title_fullStr	Albumin inhibits the nuclear translocation of Smad3 via interleukin-1beta signaling in hepatic stellate cells
title_full_unstemmed	Albumin inhibits the nuclear translocation of Smad3 via interleukin-1beta signaling in hepatic stellate cells
title_sort	albumin inhibits the nuclear translocation of smad3 via interleukin-1beta signaling in hepatic stellate cells
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/886a0473bd5e4724bb9ad46c21bd2971
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Albumin inhibits the nuclear translocation of Smad3 via interleukin-1beta signaling in hepatic stellate cells

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