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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number3196
JournalScientific reports
Volume11
Issue number1
DOIs
Publication statusPublished - 2021 Dec
Externally publishedYes

ASJC Scopus subject areas

  • General

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