Hesperetin derivative-16 attenuates CCl4-induced inflammation and liver fibrosis by activating AMPK/SIRT3 pathway

被引：40

作者：

Li, Juan-Juan ^{[1
]}

Jiang, He-Chun ^{[1
,2
]}

Wang, Ao ^{[1
]}

Bu, Fang-Tian ^{[1
]}

Jia, Peng-Cheng ^{[1
]}

Zhu, Sai ^{[1
]}

Zhu, Lin ^{[1
]}

Huang, Cheng ^{[1
]}

Li, Jun ^{[1
]}

机构：

[1] Anhui Med Univ, Sch Pharm, Anhui Inst Innovat Drugs, Inflammat & Immune Mediated Dis Lab Anhui Prov, Hefei 230032, Peoples R China

[2] USTC Anhui Prov Hosp, Affiliated Hosp 1, Hefei, Peoples R China

来源：

EUROPEAN JOURNAL OF PHARMACOLOGY | 2022年 / 915卷

基金：

中国国家自然科学基金;

关键词：

HD-16; Liver fibrosis; Inflammation; SIRT3; AMPK; HEPATIC-FIBROSIS; TARGET; INHIBITION; METABOLISM; COLCHICINE; DISEASE; CELL;

D O I：

10.1016/j.ejphar.2021.174530

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Liver fibrosis, a chronic inflammatory healing reaction, progresses to hepatocirrhosis without effective intervention. Hesperetin derivative (HD-16), a monomer compound derived from hesperitin, exerts anti-inflammatory and hepatoprotective effects against a spectrum of liver diseases. However, the anti-fibrotic potential of HD-16 in liver fibrosis and its underlying mechanism have not yet been elucidated. In this study, we investigated the anti fibrotic effect of HD-16 on mouse liver fibrosis induced by CCl4 and on LX-2 cells (human immortalized HSCs) stimulated by TGF-beta 1, in vivo and in vitro. HD-16 exerted an anti-fibrotic effect via regulation of the AMPK/SIRT3 pathway. Pharmacodynamic results showed that HD-16 alleviated the degree of injury and inflammation in CCl4- induced mouse liver fibrosis. Consistently, HD-16 also effectively inhibited the expression of alpha-SMA, Col1 alpha 1, Col3 alpha 1, and TIMP-1 in TGF-beta 1-activated LX-2 cells. Mechanistically, HD-16 promoted SIRT3 expression and activity in fibrotic liver and activated LX-2 cells. Furthermore, SIRT3 depletion attenuated the anti-fibrotic effects of HD-16. Intriguingly, HD-16 increased AMPK phosphorylation, whereas inhibition of SIRT3 expression did not affect AMPK phosphorylation. In contrast, AMPK silencing suppressed SIRT3 expression, suggesting that SIRT3 is a downstream target of AMPK in liver fibrosis. Overall, HD-16 attenuated CCl4-induced liver inflammation and fibrosis by activating the AMPK/SIRT3 pathway, and HD-16 may be a potential anti-fibrotic compound in the treatment of liver fibrosis.

引用

页数：13

共 48 条

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