NLRP3 inflammasome inhibitor CY-09 reduces hepatic steatosis in experimental NAFLD mice

Xianfei Wang; Kangyue Sun; Youlian Zhou; Hong Wang; Yongjian Zhou; Side Liu; Yuqiang Nie; Yue Li

doi:10.1016/j.bbrc.2020.11.009

NLRP3 inflammasome inhibitor CY-09 reduces hepatic steatosis in experimental NAFLD mice

Biochem Biophys Res Commun. 2021 Jan 1:534:734-739. doi: 10.1016/j.bbrc.2020.11.009. Epub 2020 Nov 16.

Authors

Xianfei Wang¹, Kangyue Sun², Youlian Zhou³, Hong Wang³, Yongjian Zhou³, Side Liu², Yuqiang Nie⁴, Yue Li⁵

Affiliations

¹ Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou Medical University, The Second Affiliated Hospital of South China University of Technology, Guangzhou, 510180, China; Department of Gastroenterology, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, China.
² Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
³ Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou Medical University, The Second Affiliated Hospital of South China University of Technology, Guangzhou, 510180, China.
⁴ Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou Medical University, The Second Affiliated Hospital of South China University of Technology, Guangzhou, 510180, China. Electronic address: eynieyuqiang@scut.edu.cn.
⁵ Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. Electronic address: liyue_1989919@126.com.

PMID: 33213837
DOI: 10.1016/j.bbrc.2020.11.009

Abstract

Aims: Non-alcoholic fatty liver disease (NAFLD) has become one of the most common chronic liver diseases. The NOD-like receptor protein 3 (NLRP3) inflammasome was suggested to be involved in the pathogenesis of NAFLD. A small-molecule named CY-09 is a new selective and direct inhibitor of the NLRP3 inflammasome. We aimed to investigate whether CY-09 is effective for the treatment of NAFLD in a high-fat diet (HFD)-induced mouse model.

Methods: Twenty mice were fed by HFD for 14 weeks, and then were randomly assigned into two groups: (1) control group receiving dimethylsulfoxide (DMSO) solution; (2) CY-09 group receiving CY-09 injection. In an 8-week follow-up, oral glucose tolerance test (OGTT) and homeostasis model assessment of insulin resistance (HOMA-IR) were used to measure glucose metabolism. Liver steatosis was evaluated by the NAFLD activity score (NAS) and deemed as the primary outcome.

Results: The body weight in CY-09 group was significantly lower than the DMSO control group on 27 weeks (41.0 ± 3.5 g vs. 49.7 ± 5.2 g, P = 0.014). The area under the curve (AUC) of OGTT was less in CY-09 group than that in DMSO group (35.81 ± 6.79 vs. 22.91 ± 2.58 mmol/L·hr, P = 0.004), as well as HOMA-IR (14.36 ± 3.89 vs. 8.82 ± 2.04 mmol.mIU.L-2, P = 0.023). Microscopically, liver lipid droplets dramatically improved and significantly lower NAS was observed in CY-09 group (8.25 ± 1.26 vs. 3.20 ± 0.45, P < 0.001).

Conclusion: CY-09 reduces hepatic steatosis in experimental NAFLD mice and CY-09 may be a potential therapeutic drug of NAFLD in clinical practice.

Keywords: CY-09; NAFLD; NLRP3 inflammasome.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Body Weight / drug effects
Diet, High-Fat / adverse effects
Disease Models, Animal
Insulin Resistance
Male
Mice
Mice, Inbred C57BL
Non-alcoholic Fatty Liver Disease / drug therapy*
Non-alcoholic Fatty Liver Disease / etiology
Non-alcoholic Fatty Liver Disease / pathology
Thiazolidines / pharmacology*
Thiones / pharmacology*
Triglycerides / blood

Substances

CY-09 compound
Thiazolidines
Thiones
Triglycerides