Physalin B attenuates liver fibrosis via suppressing LAP2α-HDAC1-mediated deacetylation of the transcription factor GLI1 and hepatic stellate cell activation

Autor:	Shengtao Ye, Xiaoyun Zhu, Meihui Zhang, Ting Yang, Ling-Yi Kong, Xin-lin Chen, Yingrong Leng, Dong‐ke Yu, Hao Zhang, Jian-Guang Luo, Jie Li, Yanqiu Zhang
Rok vydání:	2021
Předmět:	0301 basic medicine Liver Cirrhosis Histone Deacetylase 1 Zinc Finger Protein GLI1 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Western blot In vivo medicine Hepatic Stellate Cells Animals Secosteroids Hedgehog Proteins Transcription factor Carbon Tetrachloride Pharmacology integumentary system Oncogene medicine.diagnostic_test Chemistry Hepatic stellate cell activation HDAC1 030104 developmental biology Liver Hepatic stellate cell Cancer research Physalin 030217 neurology & neurosurgery Transcription Factors
Zdroj:	British journal of pharmacologyREFERENCES. 178(17)
ISSN:	1476-5381
Popis:	Background and purpose Liver fibrosis is one of the leading causes of morbidity and mortality worldwide but lacks any acceptable therapy. The transcription factor glioma-associated oncogene homologue 1 (GLI1) is a potentially important therapeutic target in liver fibrosis. This study investigates the anti-fibrotic activities and potential mechanisms of the phytochemical, physalin B. Experimental approach Two mouse models (CCl4 challenge and bile duct ligation) were used to assess antifibrotic effects of physalin B in vivo. Mouse primary hepatic stellate cells (pHSCs) and human HSC line LX-2 also served as in vitro liver fibrosis models. Liver fibrogenic genes, GLI1 and GLI1 downstream genes were examined using Western blot and quantitative real-time PCR (qRT-PCR). GLI1 acetylation and LAP2α-HDAC1 interaction were analysed by co-immunoprecipitation. Key results In vivo, physalin B administration attenuated hepatic histopathological injury and collagen accumulation and decreased expression of fibrogenic genes. Physalin B dose-dependently suppressed fibrotic marker expression in LX-2 cells and mouse pHSCs. Mechanistic studies showed that physalin B inhibited GLI activity by non-canonical Hedgehog signalling. Physalin B blocked formation of lamina-associated polypeptide 2α (LAP2α)/histone deacetylase 1 (HDAC1) complexes, thus inhibiting HDAC1-mediated GLI1 deacetylation. Physalin B up-regulated acetylation of GLI1, down-regulated expression of GLI1 and subsequently inhibited HSC activation. Conclusion and implications Physalin B exerted potent antifibrotic effects in vitro and in vivo by disrupting LAP2α/HDAC1 complexes, increasing GLI1 acetylation and inactivating GLI1. This indicates that the phytochemical physalin B may be a potential therapeutic candidate for the treatment of liver fibrosis.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::192095f64dbedd4ea200de277dc4cf88 https://pubmed.ncbi.nlm.nih.gov/33864382 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
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