GW9662 ameliorates nonalcoholic steatohepatitis by inhibiting the PPARγ/CD36 pathway and altering the gut microbiota

作者全名："Xiao, Jing; Xiang, Huanyu; Xiang, Hongyan; Sun, Zilin; Xu, Jing; Ren, Hong; Hu, Peng; Peng, Mingli"

作者地址："[Xiao, Jing; Xiang, Huanyu; Xiang, Hongyan; Sun, Zilin; Xu, Jing; Ren, Hong; Hu, Peng; Peng, Mingli] Chongqing Med Univ, Key Lab Mol Biol Infect Dis, Inst Viral Hepatitis, Dept Infect Dis,Minist Educ,Affiliated Hosp 2, Chongqing, Peoples R China"

通信作者："Hu, P; Peng, ML (通讯作者)，Chongqing Med Univ, Key Lab Mol Biol Infect Dis, Inst Viral Hepatitis, Dept Infect Dis,Minist Educ,Affiliated Hosp 2, Chongqing, Peoples R China."

来源：EUROPEAN JOURNAL OF PHARMACOLOGY

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:001105284700001

JCR分区：Q1

影响因子：4.2

年份：2023

卷号：960

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：GW9662; PPAR gamma antagonist; NASH; Gut microbiota

摘要："Background & aims: Peroxisome proliferator-activated receptors (PPARs) are currently among the most focused-on therapeutic targets for non-alcoholic steatohepatitis (NASH), although no clinical transformation has been achieved to date. In this study, we aimed to evaluate the effects of GW9662 on choline-deficient, L-amino acid-defined high-fat diet (CDAA-HFD)-induced NASH mice and reveal the mechanism underlying this effect. Methods: GW9662 (1 mg/kg) was administered in CDAA-HFD mouse model of NASH. The effect of GW9662 on hepatic lipid metabolism was investigated using liver RNA-seq and HepG2 cells induced by oleic acid and palmitic acid. In addition, 16S rRNA gene sequencing was performed to analyze the effects of GW9662 on the composition and function of the fecal microbiota. Results: GW9662 improved the CDAA-HFD caused elevation in the levels of ALT, AST, hepatic free fatty acids and triglycerides. The liver pathological analysis indicated that GW9662 alleviated the hepatic steatosis and fibrosis. The NAFLD activity score and RNA-Seq revealed that GW9662 mainly regulated the fatty acids transport and lipid synthesis by inhibiting PPAR gamma, CD36, FABP1, FASN, and SCD1, and through the up-regulation of PPAR alpha. Moreover, GW9662 reduced the epididymal fat weight. GW9662 reversed the gut microbiota disorder by increasing the abundance of the beneficial bacteria Dubosiella and Lactobacillus and decreasing the abundance of harmful bacteria Lachnospiraceae_NK4A136_group, Helicobacteraceae, Desulfovibriaceae, and Rickenaceae. Conclusions: GW9662 ameliorated lipid metabolism by inhibiting the PPAR gamma/CD36 pathway and altering the composition of the gut microbiota in NASH mice. Therefore, the PPAR gamma antagonist GW9662 deserves more attention as a potential therapeutic agent for NASH."

基金机构："pilot project of clinical cooperation between traditional Chinese and western medicine for significant and complicated diseases of National Administration of Traditional Chinese Medicine: hepatic fibrosis, Remarkable Innovation-Clinical Research Project, T"

基金资助正文："A pilot project of clinical cooperation between traditional Chinese and western medicine for significant and complicated diseases of National Administration of Traditional Chinese Medicine: hepatic fibrosis, Remarkable Innovation-Clinical Research Project, The Second Affiliated Hospital of Chongqing Medical University, The First batch of key Disciplines on Public Health in Chongqing, Health Commission of Chongqing, China."