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

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

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4 Citations (Scopus)


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.

Original languageEnglish
Article number3196
JournalScientific reports
Issue number1
Publication statusPublished - 2021 Dec
Externally publishedYes

Bibliographical note

Funding Information:
We thank Dr. Young-Sik Kim and Dr. William G. Stetler-Stevenson for encouragement and discussion. This work was supported by a Grant from the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (NRF-2017M3A9C8031617).

Publisher Copyright:
© 2021, The Author(s).

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