P7C3-A20, a novel neuroprotective agent, treats fatty liver through inducing FGFs in a LKB1/AMPK/CRTC2 pathway-dependent manner

被引：1

作者：

HUA Xia ^{[1
]}

ZHANG Wen-Jie ^{[1
]}

SUN Di-Yang ^{[1
]}

SUN Si-Jia ^{[2
]}

FU Jiang-tao ^{[1
]}

ZENG Fei-yan ^{[2
]}

OUYANG Shen-xi ^{[2
]}

ZHANG Guo-yan ^{[2
]}

LI Dong-jie ^{[2
]}

MIAO Chao-yu ^{[1
]}

WANG Pei ^{[1
,3
]}

机构：

[1] Department of Pharmacology, School of Pharmacy,Second Military Medical University

[2] Department of Pharmacy, Shanghai Tenth People's Hospital affiliated to School of Medicine, Tongji University

[3] School of Medicine, Tongji University

来源：

中国药理学与毒理学杂志 | 2019年 / 10期

基金：

中国国家自然科学基金; 国家重点研发计划;

关键词：

fatty liver; AMPK; CRTC2; FGF21; FGF1;

D O I：

暂无

中图分类号：

R965 [实验药理学];

学科分类号：

100602 ; 100706 ;

摘要：

OBJECTIVE Nonalcoholic fatty liver disease（NAFLD） is a critical worldwide public health concern with no established pharmacological therapy. The novel aminopropyl carbazole compound P7C3-A20, a member of P7C3 family, was identified to be a neuroprotective agent previously. However, the pharmacological actions of P7C3-A20 have not been ful y revealed yet. METHODS NAFLD model was induced in mice with a high-fat diet（HFD, 42% fat for energy） for 16 weeks. P7C3-A20(20 mg·kg;·d;) was administrated for 2 weeks. Indirect calorimetry,histology analysis, immunoblotting, immunohistochemistry and biomedical examinations were used to evaluate the effect of P7C3-A20. RESULTS P7C3-A20 treatment significantly reduced the body weight gain and adiposity,improved insulin resistance（glucose/insulin tolerance tests）, promoted energy expenditure（O;consumption and CO;production）, inhibited lipid peroxidation（4-hydroxynonenal and malondialdehyde）, suppressed hepatic inflammation（Kupffer cell number and pro-inflammatory factors）, decreased necroptosis and apoptosis（receptor-interacting serine-threonine kinase 3, cleaved caspase-3 and TUNEL）, and ultimately alleviated liver fibrosis and injury. Mechanically, P7C3-A20 treatment stimulated fibroblast growth factor 21（FGF21） and FGF1 via activating liver kinase B1（LKB1） and AMP-activated protein kinase（AMPK） pathway, which further resulted in a reduced nuclear translocation of CREB regulated transcription coactivator 2（CRTC2）. In AMPKa2 knockout mice, the protection of P7 C3-A20 against HFD-induced metabolism abnormities and fat accumulation, as well as the elevation of blood FGF21 and FGF1, were abolished.CONCLUSION P7 C3-A20 alleviates adiposity, metabolism abnormalities, lipid peroxidation and steatohepatitis in NAFLD through stimulating FGF21 and FGF1 in an LKB1/AMPK/CRTC2 signaling pathway-dependent manner.

引用

页码：922 / 922

页数：1