Prevention of D-GalN/LPS-induced ALI by 18 beta-glycyrrhetinic acid through PXR-mediated inhibition of autophagy degradation

doi:10.1038/s41419-021-03768-8

	Prevention of D-GalN/LPS-induced ALI by 18 beta-glycyrrhetinic acid through PXR-mediated inhibition of autophagy degradation
	Wu, Shouyan 1,2; Lu, Henglei 1,2,3; Wang, Wenjie 1,2,4; Song, Luyao 1,2; Liu, Meng 1,2; Cao, Yuhan 1,2; Qi, Xinming 1,2; Sun, Jianhua 1,2; Gong, Likun 1,2,5
刊名	CELL DEATH & DISEASE
	2021-05-13
卷号	12 期号:5 页码:13
ISSN号	2041-4889
DOI	10.1038/s41419-021-03768-8
通讯作者	Sun, Jianhua(jhsun@cdser.simm.ac.cn) ; Gong, Likun(lkgong@cdser.simm.ac.cn)
英文摘要	Acute liver injury (ALI) has multiple causes and results in liver dysfunction. Severe or persistent liver injury eventually leads to liver failure and even death. Pregnane X receptor (PXR)-null mice present more severe liver damage and lower rates of autophagy. 18 beta-glycyrrhetinic acid (GA) has been proposed as a promising hepatoprotective agent. We hypothesized that GA significantly alleivates D-GalN/LPS-induced ALI, which involved in PXR-mediated autophagy and lysosome biogenesis. We found that GA can significantly decrease hepatocyte apoptosis and increase the hepatic autophagy marker LC3-B. Ad-mCherry-GFP-LC3 tandem fluorescence, RNA-seq and real-time PCR indicated that GA may stabilize autophagosomes and lysosomes and inhibit autophagosome-lysosome fusion. Simultaneously, GA markedly activates PXR, even reversing the D-GalN/LPS-induced reduction of PXR and its downstream genes. In contrast, GA has a weak protective effect in pharmacological inhibition of PXR and PXR-null mice, which significantly affected apoptosis- and autophagy-related genes. PXR knockout interferes with the stability of autophagosomes and lysosomes, preventing GA reducing the expression of lysosomal genes such as Cst B and TPP1, and suppressing autophagy flow. Therefore, we believe that GA increases autophagy by inhibiting autophagosome-lysosome fusion and blocked autophagy flux via activation of PXR. In conclusion, our results show that GA activates PXR to regulate autophagy and lysosome biogenesis, represented by inhibiting autophagosome-lysosome fusion and stabilization of lysosome. These results identify a new mechanism by which GA-dependent PXR activation reduces D-GalN/LPS-induced acute liver injury.
资助项目	National Natural Science Foundation of China[81703806] ; National New Drug Creation Program of China[2018ZX09201017-004] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12050305] ; Post-Doctoral Science Foundation of China[2020499] ; Guangdong Province Science and Technology Plan Project[2019B020202003]
WOS关键词	PREGNANE-X-RECEPTOR ; FULMINANT HEPATIC-FAILURE ; LIVER-INJURY ; PROTECTS ; CHOLESTASIS ; LICORICE ; KINASE ; FUSION ; CELLS ; MICE
WOS研究方向	Cell Biology
语种	英语
出版者	SPRINGERNATURE
WOS记录号	WOS:000656241200001
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/297202]
专题	中国科学院上海药物研究所
通讯作者	Sun, Jianhua; Gong, Likun
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 2.Univ Chinese Acad Sci, China 100049, Peoples R China 3.Shanghai Univ Tradit Chinese Med, China 201203, Peoples R China 4.Fudan Univ, Dept Pharmacol, Shanghai 201203, Peoples R China 5.Chinese Acad Sci, Inst Drug Discovery & Dev, Zhongshan Branch, Zhongshan, Peoples R China
推荐引用方式 GB/T 7714	Wu, Shouyan,Lu, Henglei,Wang, Wenjie,et al. Prevention of D-GalN/LPS-induced ALI by 18 beta-glycyrrhetinic acid through PXR-mediated inhibition of autophagy degradation[J]. CELL DEATH & DISEASE,2021,12(5):13.
APA	Wu, Shouyan.,Lu, Henglei.,Wang, Wenjie.,Song, Luyao.,Liu, Meng.,...&Gong, Likun.(2021).Prevention of D-GalN/LPS-induced ALI by 18 beta-glycyrrhetinic acid through PXR-mediated inhibition of autophagy degradation.CELL DEATH & DISEASE,12(5),13.
MLA	Wu, Shouyan,et al."Prevention of D-GalN/LPS-induced ALI by 18 beta-glycyrrhetinic acid through PXR-mediated inhibition of autophagy degradation".CELL DEATH & DISEASE 12.5(2021):13.