Albumin inhibits the activation of hepatic stellate cells by suppressing TGF-β/Smad3 signaling via IL-1β

<jats:title>Abstract</jats:title><jats:p>Activated hepatic stellate cells (HSCs) play a key role in liver fibrosis and inactivating HSCs has been considered a promising therapeutic approach. We previously showed that albumin and its derivative, retinol binding protein (RBP)-albumin domain III fusion protein (named R-III), inhibit HSC activation. Here, we investigate the mode of action of albumin and R-III. NF-κB in activated HSCs was evenly distributed in the cytoplasm, but albumin expression and R-III treatment (albumin/R-III) induced NF-κB nuclear translocation via retinoic acid (RA) sequestration, resulting in increased expression of interleukin-1β (IL-1β). In an IL-1β dependent manner, albumin/R-III inhibited Smad3 nuclear translocation via TAK1-, JNK-mediated Smad3 linker phosphorylation and decreased expression of Smad3 target genes, such as α-smooth muscle actin and collagen type I. Mutation of the Smad3 linker phosphorylation sites abolished R-III effects on Smad3. In conclusion, our data suggest that the anti-fibrotic effects of albumin/R-III are due to RA sequestration which downregulates RAR-mediated signaling and also TGF-β/Smad3 signaling. This mechanistic elucidation of albumin function in HSCs provides clues to understanding the frequent albumin mutations found in hepatocellular carcinoma.</jats:p>