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.

Abstract

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.

• Authors: Diptadip Dattaroy, Ratanesh Kumar Seth, Sutapa Sarkar, Diana Kimono, Muayad Albadrani, Varun Chandrashekaran, Firas Al Hasson, Udai P Singh, Daping Fan, Mitzi Nagarkatti, Prakash Nagarkatti, Anna Mae Diehl, Saurabh Chatterjee
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 841 Pg. 33-48 (Dec 15 2018) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 30194936 (Publication Type: Journal Article)
• Copyright: Copyright © 2018. Published by Elsevier B.V.

Chemical References

• Cyclin E
• Cyclin-Dependent Kinase Inhibitor p21
• Fibronectins
• Heterocyclic Compounds, 4 or More Rings
• MIRN21 microRNA, human
• Membrane Proteins
• MicroRNAs
• STAT3 Transcription Factor
• Toll-Like Receptor 4
• Transforming Growth Factor beta
• Tumor Suppressor Protein p53
• sparstolonin B
• TPTE protein, human
• PTEN Phosphohydrolase

Topics

• Animals
• Apoptosis (drug effects)
• Cell Differentiation (drug effects)
• Cell Line
• Cell Proliferation (drug effects)
• Cyclin E (metabolism)
• Cyclin-Dependent Kinase Inhibitor p21 (metabolism)
• Epithelial-Mesenchymal Transition (drug effects)
• Fibroblasts (drug effects, pathology)
• Fibronectins (metabolism)
• Focal Adhesions (drug effects, metabolism)
• Hepatic Stellate Cells (drug effects, pathology)
• Heterocyclic Compounds, 4 or More Rings (pharmacology, therapeutic use)
• Humans
• Liver Cirrhosis (drug therapy, metabolism, pathology)
• Male
• Membrane Proteins (metabolism)
• Mice
• Mice, Inbred C57BL
• MicroRNAs (genetics)
• PTEN Phosphohydrolase (metabolism)
• Phosphorylation (drug effects)
• STAT3 Transcription Factor (metabolism)
• Signal Transduction (drug effects)
• Stress Fibers (drug effects, metabolism)
• Toll-Like Receptor 4 (metabolism)
• Transforming Growth Factor beta (metabolism)
• Tumor Suppressor Protein p53 (metabolism)
• Up-Regulation (drug effects)