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毛蕊异黄酮通过激活法尼醇 X 受体减轻非酒精性脂肪性肝炎小鼠模型的甘油三酯积累和肝纤维化。

Calycosin attenuates triglyceride accumulation and hepatic fibrosis in murine model of non-alcoholic steatohepatitis via activating farnesoid X receptor.

机构信息

Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian, Liaoning, China; Provincial Key Laboratory for Pharmacokinetics and Transport, Dalian, Liaoning, China.

出版信息

Phytomedicine. 2017 Feb 15;25:83-92. doi: 10.1016/j.phymed.2016.12.006. Epub 2016 Dec 13.

DOI:10.1016/j.phymed.2016.12.006

PMID:28190475

Abstract

BACKGROUND

Non-alcoholic steatohepatitis (NASH) represents the more severe end of hepatic steatosis and is associated with progressive liver disease. Calycosin, derived from the root of Radix Astragali, has been demonstrated to have favorable efficacy on acute liver injury.

PURPOSE

The present study was to investigate the hepatoprotective effect of calycosin on attenuating triglyceride accumulation and hepatic fibrosis, as well as explore the potential mechanism in murine model of NASH.

STUDY DESIGN

The C57BL/6 male mice were fed with methionine choline deficient (MCD) diet for 4 weeks to induce NASH and treated with or without calycosin by oral gavage for 4 weeks.

METHODS

The body weight, liver weight and the liver to body weight ratios were measured. Serum ALT, AST, TG, TC, FFA, MCP-1 and mKC levels were accessed by biochemical methods. H&E staining and Oil red O staining were used to identify the amelioration of liver histopathology. Immunohistochemistry of a-SMA, Masson trichrome staining and Sirius red staining were used to identify the amelioration of hepatic fibrosis. The quantitative real-time-PCR and Western blot were applied to observe the expression changes of key factors involved in triglyceride synthesis, free fatty acid β-oxidation and hepatic fibrosis.

RESULTS

Calycosin significantly inhibited body weight loss induced by MCD diet, decreased the ALT and AST activities, MCP-1 and mKC in a dose-dependent manner. The H&E and Oil red O staining indicated calycosin effectively improved hepatic steatosis, improved the degree of triglyceride accumulation. Masson trichrome and Sirius red staining indicated that calycosin treatment remarkably attenuated the degree of hepatic fibrosis. Immunohistochemistry of a-SMA demonstrated that calycosin attenuated hepatic fibrosis by inhibiting hepatic stellate cell activation. Further, calycosin inhibited the expression of SREBP-1c, FASN, ACC and SCD1 involved in triglyceride synthesis, promoted the expression of PPARa, CPT1, Syndecan-1 and LPL involved in free fatty acid β-oxidation. The above effects of calycosin were attributed to FXR activation.

CONCLUSION

Calycosin attenuates triglyceride accumulation and hepatic fibrosis to protect against NASH via FXR activation.

摘要

背景

非酒精性脂肪性肝炎（NASH）代表了肝脏脂肪变性更严重的阶段，与进行性肝病有关。毛蕊异黄酮来源于黄芪根，已被证明对急性肝损伤有良好的疗效。

目的

本研究旨在探讨毛蕊异黄酮通过减轻甘油三酯积累和肝纤维化来保护肝脏的作用，并探讨其在 NASH 小鼠模型中的潜在机制。

研究设计

雄性 C57BL/6 小鼠用蛋氨酸胆碱缺乏（MCD）饮食喂养 4 周，以诱导 NASH，并通过口服灌胃给予毛蕊异黄酮或不给予毛蕊异黄酮治疗 4 周。

方法

测量体重、肝重和肝重与体重比。通过生化方法检测血清 ALT、AST、TG、TC、FFA、MCP-1 和 mKC 水平。使用 H&E 染色和油红 O 染色来确定肝组织病理学的改善情况。使用 α-SMA、Masson 三色染色和天狼猩红染色的免疫组化来确定肝纤维化的改善情况。应用实时定量 PCR 和 Western blot 观察参与甘油三酯合成、游离脂肪酸 β-氧化和肝纤维化的关键因子的表达变化。

结果

毛蕊异黄酮显著抑制 MCD 饮食诱导的体重减轻，呈剂量依赖性降低 ALT 和 AST 活性、MCP-1 和 mKC。H&E 和油红 O 染色表明毛蕊异黄酮有效改善了肝脂肪变性，改善了甘油三酯积累程度。Masson 三色和天狼猩红染色表明，毛蕊异黄酮治疗显著减轻了肝纤维化程度。α-SMA 的免疫组化表明，毛蕊异黄酮通过抑制肝星状细胞活化来减轻肝纤维化。此外，毛蕊异黄酮抑制了参与甘油三酯合成的 SREBP-1c、FASN、ACC 和 SCD1 的表达，促进了参与游离脂肪酸 β-氧化的 PPARa、CPT1、Syndecan-1 和 LPL 的表达。毛蕊异黄酮的上述作用归因于 FXR 的激活。