Improvement effects and mechanism of sinomenine on non-alcoholic steatohepatitis in mice

ZENG Cheng; WENG Liangkun

doi:10.6039/j.issn.1001-0408.2024.14.05

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Improvement effects and mechanism of sinomenine on non-alcoholic steatohepatitis in mice

更新时间：2024-07-25

- Improvement effects and mechanism of sinomenine on non-alcoholic steatohepatitis in mice
- ZHONGGUO YAOFANG Vol. 35, Issue 14, Pages: 1701-1707(2024)
- 作者机构：
  
  1.广东药科大学附属第一医院临床药学重点专科，广州　510699
  2.广东药科大学新药研发中心，广州　510006
- 作者简介：
- 基金信息：
- DOI：10.6039/j.issn.1001-0408.2024.14.05
  CLC： R965
- Published：30 July 2024，
  
  Received：29 December 2023，
  
  Revised：09 May 2024，
- 稿件说明：
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曾诚,翁良坤.青藤碱对小鼠非酒精性脂肪性肝炎的改善作用及机制 ^Δ[J].中国药房,2024,35(14):1701-1707.

ZENG Cheng,WENG Liangkun.Improvement effects and mechanism of sinomenine on non-alcoholic steatohepatitis in mice[J].ZHONGGUO YAOFANG,2024,35(14):1701-1707.
曾诚,翁良坤.青藤碱对小鼠非酒精性脂肪性肝炎的改善作用及机制 ^Δ[J].中国药房,2024,35(14):1701-1707. DOI： 10.6039/j.issn.1001-0408.2024.14.05.

ZENG Cheng,WENG Liangkun.Improvement effects and mechanism of sinomenine on non-alcoholic steatohepatitis in mice[J].ZHONGGUO YAOFANG,2024,35(14):1701-1707. DOI： 10.6039/j.issn.1001-0408.2024.14.05.

摘要

目的

探究青藤碱（Sin）对非酒精性脂肪性肝炎（NASH）的改善作用及潜在机制。

方法

以雄性C57BL/6J小鼠为对象，将其随机分为标准饲料（SCD）组、高脂饲料（HFD）组、Sin低剂量组（Sin-L组，50 mg/kg）、Sin高剂量组（Sin-H组，100 mg/kg），每组6只。SCD组小鼠以SCD正常喂养，其余组小鼠均以HFD连续饲养24周以复制NASH模型；于17周起，各药物组小鼠分别灌胃相应药液，每天1次，连续8周。末次给药后，称定各组小鼠体重、肝脏质量并计算肝脏指数；检测其肝组织中总胆固醇（TC）、甘油三酯（TG）含量和血清中天冬氨酸转移酶（AST）、丙氨酸转氨酶（ALT）、白细胞介素1β（IL-1β）、IL-18含量；观察其肝细胞脂肪变性、肝纤维化，并定位肝脏脂滴；检测其IL-18、IL-1β mRNA和炎症相关蛋白[IL-1β、剪切的IL-1β（cleaved-IL-1β）

]

、纤维化相关蛋白[Ⅰ型胶原蛋白（Col-Ⅰ）、

-平滑肌肌动蛋白（

-SMA）、结缔组织生长因子（CTGF）

]

、通路相关蛋白[腺苷一磷酸活化的蛋白激酶（AMPK）、磷酸化AMPK（p-AMPK）、Yes相关蛋白（YAP）、磷酸化YAP（p-YAP）

]

的表达情况。以人肝癌细胞HepG2为对象，将其分为对照组、油酸（OA）组、Sin 50 μmol/L组、Sin 100 μmol/L组、OA+Sin 50 μmol/L组和OA+Sin 100 μmol/L组，处理24 h后，观察其脂滴蓄积情况，并检测其通路相关蛋白的表达情况。

结果

与HFD组比较，Sin各剂量组小鼠的肝细胞脂肪变性、纤维化病变和脂滴蓄积均有所缓解；其体重，肝脏质量，肝脏指数（Sin-L组除外），血清AST、ALT、IL-1β、IL-18含量，肝组织中TG、TC含量，IL-1β、IL-18 mRNA的表达水平，以及cleaved-IL-1β蛋白和纤维化相关蛋白的表达水平均显著降低（

＜0.01）；肝组织中IL-1β蛋白的表达水平和AMPK、YAP蛋白的磷酸化水平均显著升高（

＜0.01）。与OA组比较，OA+Sin各浓度组细胞的脂滴蓄积均明显减少，AMPK、YAP蛋白的磷酸化水平均显著升高（

＜0.05）。

结论

Sin可改善NASH小鼠肝组织的炎症反应、脂质沉积和纤维化，其机制可能与激活AMPK信号通路、促进YAP蛋白磷酸化相关。

Abstract

OBJECTIVE

To investigate the improvement effects of sinomenine （Sin） on non-alcoholic steatohepatitis （NASH） and its potential mechanism.

METHODS

Male C57BL/6J mice were randomly divided into standard chow diet （SCD） group， high-fat diet （HFD） group， Sin low-dose group （Sin-L group， 50 mg/kg）， and Sin high-dose group （Sin-H group， 100 mg/kg）， with 6 mice

in each group. The mice of SCD groups were fed with SCD， and other groups were given HFD for consecutive 24 weeks to establish NASH model. Since 17th week， the mice in each drug group were given corresponding drug solutions intragastrically， once a day， for 8 consecutive weeks. After the last medication， the body weight and liver weight of mice were determined， and liver indexes were calculated. The contents of total cholesterol （TC） and triglyceride （TG） in liver tissue， the serum contents of aspartate aminotransferase （AST）， alanine aminotransferase （ALT）， interleukin-1β （IL-1β） and IL-18 were all determined. Hepatic steatosis and fibrosis were observed， and hepatic lipid droplets were located. The expressions of IL-18 and IL-1β mRNA， inflammation-related proteins （IL-1β， cleaved-IL-1β）， fibrosis-related proteins [collagen Ⅰ （Col-Ⅰ），

-smooth muscle actin （

-SMA）， connective tissue growth factor （CTGF）

]

， and pathway-related protein [adenosine monophosphate-activated protein kinase （AMPK）， phosphorylated AMPK （p-AMPK）， Yes-associated protein （YAP）， phosphorylated YAP （p-YAP）

]

were all determined. HepG2 human liver cancer cells were selected as subjects and divided into control group， oleic acid （OA） group， Sin 50 μmol/L group， Sin 100 μmol/L group， OA+Sin 50 μmol/L group and OA+Sin 100 μmol/L group. After 24 hours of treatment， the accumulation of lipid droplets was observed， and the expressions of pathway-related proteins were detected.

RESULTS

Compared to HFD group， hepatic steatosis， fibrotic lesions and lipid droplet accumulation were all alleviated in Sin groups； body weight， liver weight， liver indexes， the contents of AST， ALT， IL-1β， IL-18 in serum and TG， TC in liver tissue， the mRNA expressions of IL-1β and IL-18， and the expressions of cleaved-IL-1β and fibrosis-related proteins all decreased significantly （

＜0.01）； the protein expression of IL-1β， and the phosphorylation levels of AMPK and YAP proteins significantly in

creased （

＜0.01）. Compared with OA group， the lipid droplet accumulation of cells in OA+Sin groups significantly decreased， while the phosphorylation levels of AMPK and YAP proteins significantly increased （

＜0.05）.

CONCLUSIONS

Sin can ameliorate the inflammation， lipid deposition and fibrosis of liver tissue in mice， the mechanism of which may be associated with activating the AMPK signaling pathway and promoting YAP phosphorylation.

关键词

非酒精性脂肪性肝炎青藤碱腺苷一磷酸活化的蛋白激酶Yes相关蛋白炎症反应

Keywords

sinomenineAMPKYAPinflammatory reaction

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