Melatonin attenuates cholestatic liver injury by improving bile acid metabolism in mice

Hongjia ZHANG; Ya TAN; Nan ZHAO; Jin CHAI

doi:10.16016/j.2097-0927.202309022

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Melatonin attenuates cholestatic liver injury by improving bile acid metabolism in mice

Basic Medicine | 更新时间：2026-01-09

- Melatonin attenuates cholestatic liver injury by improving bile acid metabolism in mice
- Journal of Army Medical University Vol. 46, Issue 11, Pages: 1187-1193(2024)
- 作者机构：
  
  400038 重庆，陆军军医大学(第三军医大学)第一附属医院消化内科，全军消化病研究所胆汁淤积肝病中心，代谢相关脂肪性肝病中心
- 作者简介：
- 基金信息：
  
  the Special Project of Science and Technology Innovation Capacity Promotion of Army Medical University(2022XQN19)
- DOI：10.16016/j.2097-0927.202309022
  CLC： R333.3;R575;R977.1
- Received：04 September 2023，
  
  Revised：2024-01-11，
  
  Published：15 June 2024
- 稿件说明：
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Hongjia ZHANG, Ya TAN, Nan ZHAO, et al. Melatonin attenuates cholestatic liver injury by improving bile acid metabolism in mice[J]. Journal of Army Medical University, 2024, 46(11): 1187-1193.
DOI：

Hongjia ZHANG, Ya TAN, Nan ZHAO, et al. Melatonin attenuates cholestatic liver injury by improving bile acid metabolism in mice[J]. Journal of Army Medical University, 2024, 46(11): 1187-1193. DOI： 10.16016/j.2097-0927.202309022.

摘要

目的

初步探究褪黑素(melatonin

Mel)减轻胆酸(cholic acid，CA)诱导的胆汁淤积肝损伤的机制。

方法

将15只8周龄雄性C57BL/6J小鼠按随机数字表法分为3组(

=5)：对照组、1%CA组和1%CA+Mel组，对照组喂养正常饮食，1%CA组和1%CA+Mel组喂养1%CA饮食14 d构建胆汁淤积小鼠模型，1%CA+Mel组同时腹腔注射褪黑素(100 mg/kg)。对1%CA组和1%CA+Mel组小鼠的肝组织进行α-SMA免疫组化染色，采用RT-qPCR检测小鼠肝纤维化相关指标的mRNA表达水平。采用液相色谱-串联质谱联用技术检测肝脏总胆汁酸，自动生化分析仪检测血清总胆汁酸。为了进一步了解胆汁酸代谢的机制，采用RT-qPCR检测小鼠胆汁酸合成和肝脏解毒酶相关指标的mRNA表达水平，Western blot检测胆汁酸合成和肝脏解毒酶相关指标的蛋白表达水平。

结果

与1%CA组相比，1%CA+ Mel组的小鼠肝纤维化相关指标Tgfβ1、Col Ⅰ a1、Col Ⅱ a1和α-SMA的mRNA表达水平明显降低(

0.05)，小鼠肝组织α-SMA免疫组化染色结果显示肝星状细胞活化明显减少。与1%CA组相比，1%CA+ Mel组小鼠血清与肝脏中胆汁酸含量显著减少，其中TCA含量显著降低，胆汁酸合成酶胆固醇7α-羟化酶(cholesterol 7α-hydroxylase，Cyp7a1)和Cyp8b1的mRNA水平均显著降低，肝脏解毒酶Cyp2b10和尿苷二磷酸葡萄糖醛基酶1A1(udp-glucuronosyltransferase

Ugt1a1)的mRNA水平明显升高，Cyp2b10和胆盐磺基转移酶(sulfotransferase family 2A member 1

Sult2a1/2)的蛋白水平明显升高(

0.05)。

结论

褪黑素通过减少胆汁酸合成和增加肝脏解毒酶的方式改善胆汁淤积。

Abstract

Objective

To explore the mechanism of melatonin (Mel) alleviating cholestatic liver injury in a mouse cholestasis model induced by cholic acid (CA) feeding.

Methods

A total of 15 8-week-old male C57BL/6J mice were randomly divided into control group

1%CA group

and 1%CA+Mel group

with 5 animals in each group. The control group was fed with normal chow diet

and the other 2 groups were fed with a diet containing 1%CA for 14 d to construct a model of cholestasis

and intraperitoneal injection with 100 mg/kg Mel was given to the mice from the 1%CA+Mel group. Immunohistochemical assay of α-SMA was applied for the liver tissues in the 1%CA group and the 1%CA+Mel group. The mRNA expression levels of fibrosis-related indicators in mouse liver tissue were examined by RT-qPCR. Liquid chromatography tandem mass spectrometry (LC-MS/MS) and automated biochemical analyzer were used to detect the contents of bile acids in the liver tissues and the serum of mouse

respectively. Then real-time qPCR and Western blotting were applied to detect the expression of bile acid synthesis and liver detoxification enzymes related indicators at mRNA and protein levels

respectively

to further investigate the mechanism of bile acid metabolism.

Results

Compared with the 1%CA group

the mRNA levels of liver fibrosis indicators (such as Tgfβ1

ColⅠa1

ColⅡa1 and α-SMA) were significantly reduced (

0.05)

and activation of stellate cells was obviously weakened displayed by immunohistochemical staining in the 1%CA+Mel group. The 1%CA+Mel group had notably decreased contents of bile acids in the serum and liver tissues

especially taurocholic acid and reduced mRNA levels of cholesterol 7α-hydroxylase (Cyp7a1) and Cyp8b1

while enhanced mRNA levels of hepatic detoxification enzymes Cyp2b10 and udp-glucuronosyltransferase (Ugt1a1) as well as protein levels of Cyp2b10 and sulfotransferase family 2A member 1 (Sult2a1/2) when compared with the 1%CA group (

0.05).

Conclusion

Mel exerts its therapeutic effect on cholestasis by decreasing bile acid synthesis and increasing hepatic detoxification enzymes.

关键词

Keywords

references

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Center for Metabolic Liver Diseases and Center for Cholestatic Liver Diseases, Department of Gastroenterology, First Affiliated Hospital, Army Medical University (Third Military Medical University)

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