Differential TM4SF5-mediated SIRT1 modulation and signaling for chronic liver disease

Ryu, J.; Kim, E. M.; Kang, M.; Song, D.-G.; Shin, E.-A.; Jung, J. W.; Nam, S.-H.; Kim, J. E.; Kim, H.-J.; Lee, J.-H.; Yoon, J.-H.; Son, T.; Kim, S.; Kim, H. Y.; Lee, J. W.

doi:10.1101/2020.02.19.956151

bioRxiv · 10.1101/2020.02.19.956151

Differential TM4SF5-mediated SIRT1 modulation and signaling for chronic liver disease

Ryu, J.·Kim, E. M.·Kang, M.·Song, D.-G.·Shin, E.-A.·Jung, J. W.·Nam, S.-H.·Kim, J. E.·Kim, H.-J.·Lee, J.-H.·Yoon, J.-H.·Son, T.·Kim, S.·Kim, H. Y.·Lee, J. W.

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Abstract

Here we show the roles of transmembrane 4 L six family member 5 (TM4SF5) in the progression of nonalcoholic steatosis (or NAFL) to steatohepatitis (NASH). The overexpression of TM4SF5 caused nonalcoholic steatosis and NASH in an age-dependent manner. Initially, TM4SF5-positive hepatocytes and livers exhibited lipid accumulation, decreased SIRT1, increased SREBPs levels, and inactive STAT3 via SOCS1/3 upregulation. In older animals, TM4SF5 under an inflammatory environment increased SIRT1 expression and STAT3 activity with no significant change to SOCSs and SREBPs levels, leading to active STAT3-mediated fibrotic extracellular matrix (ECM) production. Liver tissues from clinical human patients with NAFL or NASH also showed such a TM4SF5-SIRT1-STAT3-ECM relationship correlated with fibrosis score and age. Ligand-independent and TM4SF5-mediated STAT3 activity led to collagen I and laminins/laminin {gamma}2 expression in hepatic stellate cells and hepatocytes, respectively. Laminin {gamma}2 suppression abolished CCl4-mediated liver damage and ECM production and reduced SIRT1 and active-STAT3, but did not alter SREBP1 or SOCSs levels. These findings suggest that TM4SF5, CCL20, SIRT1, and/or laminin {gamma}2 may be promising therapeutic targets against liver disease.

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Ryu, J., Kim, E. M., Kang, M., Song, D.-G., Shin, E.-A., Jung, J. W., Nam, S.-H., Kim, J. E., Kim, H.-J., Lee, J.-H., Yoon, J.-H., Son, T., Kim, S., Kim, H. Y., Lee, J. W.. 2020-02-19. Differential TM4SF5-mediated SIRT1 modulation and signaling for chronic liver disease. https://doi.org/10.1101/2020.02.19.956151

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