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

Oh, J. S.; Park, J. H.; Kim, J.; Choi, S.-Y.; Cha, K.; Park, H.; Lee, J.-E.; Lee, B.; Moon, J. W.; Park, S.-H.; Lee, J. M.; Lee, H.

doi:10.1101/753152

bioRxiv · 10.1101/753152

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

Oh, J. S.·Park, J. H.·Kim, J.·Choi, S.-Y.·Cha, K.·Park, H.·Lee, J.-E.·Lee, B.·Moon, J. W.·Park, S.-H.·Lee, J. M.·Lee, H.

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Abstract

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-{kappa}B in activated HSCs was evenly distributed in the cytoplasm, but albumin expression and R-III treatment (albumin/R-III) induced NF-{kappa}B nuclear translocation via retinoic acid (RA) sequestration, resulting in increased expression of interleukin-1{beta} (IL-1{beta}). In an IL-1{beta} 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 -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-{beta}/Smad3 signaling. This mechanistic elucidation of albumin function in HSCs provides clues to understanding the frequent albumin mutations found in hepatocellular carcinoma.

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Oh, J. S., Park, J. H., Kim, J., Choi, S.-Y., Cha, K., Park, H., Lee, J.-E., Lee, B., Moon, J. W., Park, S.-H., Lee, J. M., Lee, H.. 2019-08-31. Albumin inhibits the activation of hepatic stellate cells by suppressing TGF-β/Smad3 signaling via IL-1β. https://doi.org/10.1101/753152

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