A new mechanism of obeticholic acid on NASH treatment by inhibiting NLRP3 inflammasome activation in macrophage

doi:10.1016/j.metabol.2021.154797

	A new mechanism of obeticholic acid on NASH treatment by inhibiting NLRP3 inflammasome activation in macrophage
	Huang, Suling 1; Wu, Yanwei 2; Zhao, Zhuohui 1,3; Wu, Bing 2,3; Sun, Kai 1,3; Wang, Haoyu 2,3; Qin, Li 1; Bai, Fang 2,3; Leng, Ying 1; Tang, Wei 2
刊名	METABOLISM-CLINICAL AND EXPERIMENTAL
	2021-07-01
卷号	120 页码:12
关键词	Macrophage NLRP3 inflammasome Hepatic lipid accumulation NASH FXR
ISSN号	0026-0495
DOI	10.1016/j.metabol.2021.154797
通讯作者	Leng, Ying(yleng@simm.ac.cn) ; Tang, Wei(tangwei@simm.ac.cn)
英文摘要	Objective: Obeticholic acid (OCA) has been proved to play potential therapeutic effect on nonalcoholic steatohepatitis (NASH). Up to now, the study of OCA on NLRP3 inflammasome activation in macrophage is still blank and merits great attention. Here, we aimed to better characterize the role and mechanism of OCA on NASH treatment focusing on NLRP3 inflammasome activation in macrophages. Methods: The effects of OCA on inflammasome activation were investigated in BMDM, Kupffer cell, BMDC and LX2 cell. Preconditioned media from BMDM culture was used to treat primary hepatocytes to explore the effects of macrophage NLRP3 inflammasome activation on the function of hepatocytes. In vivo, high fat diet plus CCl4 (DIO + CCl4) induced murine NASH model and choline-deficient and amino acid-defined (CDA) diet-induced NASH mice were used to verify the inhibitory effect of OCA on inflammasome activation in liver macrophages and recapitulate its protective role on NASH progressing. To clear up the effect of OCA on macrophage is FXR dependent or not, FXR siRNA was introduced into BMDMs. Results: OCA blockaded NLRP3 inflammasome in BMDMs by impacting on the activation stage and disrupting ASC oligomerization. Preconditioned supernatant from LPS + ATP treated BMDMs increased mRNA expression of lipogenic enzymes and lipid content, whereas preconditioned supernatant from OCA treated BMDM blocked these effects in both normal and the FXR knockdown hepatocytes. In DIO + CCl4 mice, the population of inflammatory myeloid lineage cells in livers was decreased upon OCA treatment. Accordingly, the level of IL-1 beta and IL-18 in liver, the hepatic expression of ASC, pro-caspase-1 and active caspase-1, the expression of caspase 1 p20 in liver macrophages were also reduced. Similar results were obtained in CDA diet-fed mice. Furthermore, OCA maintained the inhibition on NLRP3 inflammasome activation in FXR knockdown BMDMs, suggesting FXR could be dispensable in this effect. Conclusions: This finding brings up a new mechanism of OCA on NASH treatment, suggested by direct inhibition on NLRP3 inflammasome activation in macrophage, further suppression on inflammasome activation-elicited hepatic lipid accumulation, and contributing to the amelioration of NASH. (C) 2021 Elsevier Inc. All rights reserved.
资助项目	Shanghai Committee of Science and Technology, China[20ZR1468300] ; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences[SIMM2004KF-15]
WOS关键词	NONALCOHOLIC STEATOHEPATITIS ; LIVER INFLAMMATION ; FIBROSIS ; DIET
WOS研究方向	Endocrinology & Metabolism
语种	英语
出版者	W B SAUNDERS CO-ELSEVIER INC
WOS记录号	WOS:000662264900006
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/297123]
专题	中国科学院上海药物研究所
通讯作者	Leng, Ying; Tang, Wei
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Lab Antiinflammat, Shanghai 201203, Peoples R China 3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
推荐引用方式 GB/T 7714	Huang, Suling,Wu, Yanwei,Zhao, Zhuohui,et al. A new mechanism of obeticholic acid on NASH treatment by inhibiting NLRP3 inflammasome activation in macrophage[J]. METABOLISM-CLINICAL AND EXPERIMENTAL,2021,120:12.
APA	Huang, Suling.,Wu, Yanwei.,Zhao, Zhuohui.,Wu, Bing.,Sun, Kai.,...&Tang, Wei.(2021).A new mechanism of obeticholic acid on NASH treatment by inhibiting NLRP3 inflammasome activation in macrophage.METABOLISM-CLINICAL AND EXPERIMENTAL,120,12.
MLA	Huang, Suling,et al."A new mechanism of obeticholic acid on NASH treatment by inhibiting NLRP3 inflammasome activation in macrophage".METABOLISM-CLINICAL AND EXPERIMENTAL 120(2021):12.