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Sparstolonin B (SsnB) attenuates liver fibrosis via a parallel conjugate pathway involving P53-P21 axis, TGF-beta signaling and focal adhesion that is TLR4 dependent.

Publication ,  Journal Article
Dattaroy, D; Seth, RK; Sarkar, S; Kimono, D; Albadrani, M; Chandrashekaran, V; Hasson, FA; Singh, UP; Fan, D; Nagarkatti, M; Nagarkatti, P ...
Published in: Eur J Pharmacol
December 15, 2018

SsnB previously showed a promising role to lessen liver inflammation observed in a mouse model of NAFLD. Since NAFLD can progress to fibrosis, studies were designed to unravel its role in attenuating NAFLD associated fibrosis. Using both in vivo and in vitro approaches, the study probed the possible mechanisms that underlined the role of SsnB in mitigating fibrosis. Mechanistically, SsnB, a TLR4 antagonist, decreased TLR4-PI3k akt signaling by upregulating PTEN protein expression. It also decreased MDM2 protein activation and increased p53 and p21 gene and protein expression. SsnB also downregulated pro-fibrogenic hedgehog signaling pathway, inhibited hepatic stellate cell proliferation and induced apoptosis in hepatic stellate cells, a mechanism that was LPS dependent. Further, SsnB decreased fibrosis by antagonizing TLR4 induced TGFβ signaling pathway. Alternatively, SsnB augmented BAMBI (a TGFβ pseudo-receptor) expression in mice liver by inhibiting TLR4 signaling pathway and thus reduced TGFβ signaling, resulting in decreased hepatic stellate cell activation and extracellular matrix deposition. In vitro experiments on human hepatic stellate cell line showed that SsnB increased gene and protein expression of BAMBI. It also decreased nuclear co-localization of phospho SMAD2/3 and SMAD4 protein and thus attenuated TGFβ signaling in vitro. We also observed a significant decrease in phosphorylation of SMAD2/3 protein, decreased STAT3 activation, alteration of focal adhesion protein and stress fiber disassembly upon SsnB administration in hepatic stellate cells which further confirmed the antagonistic effect of SsnB on TLR4-induced fibrogenesis.

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Published In

Eur J Pharmacol

DOI

EISSN

1879-0712

Publication Date

December 15, 2018

Volume

841

Start / End Page

33 / 48

Location

Netherlands

Related Subject Headings

  • Up-Regulation
  • Tumor Suppressor Protein p53
  • Transforming Growth Factor beta
  • Toll-Like Receptor 4
  • Stress Fibers
  • Signal Transduction
  • STAT3 Transcription Factor
  • Phosphorylation
  • Pharmacology & Pharmacy
  • PTEN Phosphohydrolase
 

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Dattaroy, D., Seth, R. K., Sarkar, S., Kimono, D., Albadrani, M., Chandrashekaran, V., … Chatterjee, S. (2018). Sparstolonin B (SsnB) attenuates liver fibrosis via a parallel conjugate pathway involving P53-P21 axis, TGF-beta signaling and focal adhesion that is TLR4 dependent. Eur J Pharmacol, 841, 33–48. https://doi.org/10.1016/j.ejphar.2018.08.040
Dattaroy, Diptadip, Ratanesh Kumar Seth, Sutapa Sarkar, Diana Kimono, Muayad Albadrani, Varun Chandrashekaran, Firas Al Hasson, et al. “Sparstolonin B (SsnB) attenuates liver fibrosis via a parallel conjugate pathway involving P53-P21 axis, TGF-beta signaling and focal adhesion that is TLR4 dependent.Eur J Pharmacol 841 (December 15, 2018): 33–48. https://doi.org/10.1016/j.ejphar.2018.08.040.
Dattaroy D, Seth RK, Sarkar S, Kimono D, Albadrani M, Chandrashekaran V, et al. Sparstolonin B (SsnB) attenuates liver fibrosis via a parallel conjugate pathway involving P53-P21 axis, TGF-beta signaling and focal adhesion that is TLR4 dependent. Eur J Pharmacol. 2018 Dec 15;841:33–48.
Dattaroy, Diptadip, et al. “Sparstolonin B (SsnB) attenuates liver fibrosis via a parallel conjugate pathway involving P53-P21 axis, TGF-beta signaling and focal adhesion that is TLR4 dependent.Eur J Pharmacol, vol. 841, Dec. 2018, pp. 33–48. Pubmed, doi:10.1016/j.ejphar.2018.08.040.
Dattaroy D, Seth RK, Sarkar S, Kimono D, Albadrani M, Chandrashekaran V, Hasson FA, Singh UP, Fan D, Nagarkatti M, Nagarkatti P, Diehl AM, Chatterjee S. Sparstolonin B (SsnB) attenuates liver fibrosis via a parallel conjugate pathway involving P53-P21 axis, TGF-beta signaling and focal adhesion that is TLR4 dependent. Eur J Pharmacol. 2018 Dec 15;841:33–48.
Journal cover image

Published In

Eur J Pharmacol

DOI

EISSN

1879-0712

Publication Date

December 15, 2018

Volume

841

Start / End Page

33 / 48

Location

Netherlands

Related Subject Headings

  • Up-Regulation
  • Tumor Suppressor Protein p53
  • Transforming Growth Factor beta
  • Toll-Like Receptor 4
  • Stress Fibers
  • Signal Transduction
  • STAT3 Transcription Factor
  • Phosphorylation
  • Pharmacology & Pharmacy
  • PTEN Phosphohydrolase