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Physalin B attenuates liver fibrosis via suppressing LAP2α-HDAC1 mediated deacetylation of GLI1 and hepatic stellate cell activation
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  • Xiaoyun Zhu,
  • Shengtao Ye,
  • Jie Li,
  • Meihui Zhang,
  • Yanqiu Zhang,
  • Yingrong Leng,
  • Ting Yang,
  • xinlin Chen,
  • Jianguang Luo,
  • Hao Zhang,
  • LY Kong
Xiaoyun Zhu
China Pharmaceutical University
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Shengtao Ye
China Pharmaceutical University
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Jie Li
China Pharmaceutical University
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Meihui Zhang
China Pharmaceutical University
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Yanqiu Zhang
China Pharmaceutical University
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Yingrong Leng
China Pharmaceutical University
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Ting Yang
China Pharmaceutical University
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xinlin Chen
China Pharmaceutical University
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Jianguang Luo
China Pharmaceutical University
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Hao Zhang
China Pharmaceutical University
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LY Kong
China Pharmaceutical University
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Abstract

Background and Purpose: Liver fibrosis is one of the leading causes of morbidity and mortality worldwide of which no acceptable therapy exists. Accumulating evidence supports that glioma-associated oncogene homologue 1(GLI1) is a potentially important therapeutic target for liver fibrosis. This study investigates the antifibrotic activities and potential mechanisms of Physalin B (PB), a natural Solanaceae compound. Experimental Approach: Mice subjected to CCl4 challenge and bile duct ligation were used to study the antifibrotic effects of PB in vivo. Mouse primary hepatic stellate cells (pHSCs) and human HSC line LX‐2 also served as an in vitro liver fibrosis model. Liver fibrogenic genes, GLI1 downstream genes were examined using western blot and real-time PCR analyses. GLI1 acetylation and LAP2α-HDAC1 interaction were analyzed by coimmunoprecipitation. Key Results: In animal models, PB administration attenuated hepatic histopathological injury, collagen accumulation, and reduced the expression of fibrogenic genes. PB dose‐dependently suppressed fibrotic marker expression in LX‐2 cells and mouse pHSCs. Mechanistic studies showed PB inhibited GLI activity in a non-canonical Hedgehog signaling. PB blocked lamina-associated polypeptide 2 α (LAP2α)/ histone deacetylase 1 (HDAC1) complex formation thereby inhibited HDAC1mediated GLI1 deacetylation. PB downregulated the acetylation and expression of GLI1, and subsequently inhibiting HSC activation. Conclusions and Implications: PB exerted potent antifibrotic effects in vitro and in vivo by disrupting the LAP2α/HDAC1 complex, increasing GLI1 acetylation and inactivating GLI1. This indicates that PB may be a potential therapeutic candidate for the treatment of liver fibrosis.

Peer review status:ACCEPTED

02 Dec 2020Submitted to British Journal of Pharmacology
02 Dec 2020Submission Checks Completed
02 Dec 2020Assigned to Editor
12 Dec 2020Reviewer(s) Assigned
23 Dec 2020Review(s) Completed, Editorial Evaluation Pending
02 Jan 2021Editorial Decision: Revise Minor
20 Mar 20211st Revision Received
21 Mar 2021Submission Checks Completed
21 Mar 2021Assigned to Editor
23 Mar 2021Reviewer(s) Assigned
02 Apr 2021Review(s) Completed, Editorial Evaluation Pending
06 Apr 2021Editorial Decision: Accept