Berberine Inhibits Atherosclerosis by Regulating Lipophagy Via Targeting Wnt5a/NPC1 Signaling Pathway

YANG Caiyun; LU Qiwen; LUO Sang; TU Mengting; ZHAO Tong; ZHENG Cuicui; WAN Qiang

doi:10.13422/j.cnki.syfjx.20230936

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Berberine Inhibits Atherosclerosis by Regulating Lipophagy Via Targeting Wnt5a/NPC1 Signaling Pathway

更新时间：2023-08-22

- Berberine Inhibits Atherosclerosis by Regulating Lipophagy Via Targeting Wnt5a/NPC1 Signaling Pathway
- Chinese Journal of Experimental Traditional Medical Formulae Vol. 29, Issue 18, Pages: 62-68(2023)
- 作者机构：
  
  1.江西中医药大学附属洪都中医院，南昌 330006
  2.江西中医药大学，南昌 330004
  3.江西中医药大学附属医院，南昌 330006
- 作者简介：
- 基金信息：
- DOI：10.13422/j.cnki.syfjx.20230936
  CLC： R2-0;R33;R972+.6;R289
- Published：20 September 2023，
  
  Published Online：19 July 2023，
  
  Received：16 May 2023，
- 稿件说明：
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杨彩云,鲁启文,罗桑等.小檗碱靶向Wnt5a/NPC1信号通路调节脂自噬抑制动脉粥样硬化形成[J].中国实验方剂学杂志,2023,29(18):62-68.

YANG Caiyun,LU Qiwen,LUO Sang,et al.Berberine Inhibits Atherosclerosis by Regulating Lipophagy Via Targeting Wnt5a/NPC1 Signaling Pathway[J].Chinese Journal of Experimental Traditional Medical Formulae,2023,29(18):62-68.
杨彩云,鲁启文,罗桑等.小檗碱靶向Wnt5a/NPC1信号通路调节脂自噬抑制动脉粥样硬化形成[J].中国实验方剂学杂志,2023,29(18):62-68. DOI： 10.13422/j.cnki.syfjx.20230936.

YANG Caiyun,LU Qiwen,LUO Sang,et al.Berberine Inhibits Atherosclerosis by Regulating Lipophagy Via Targeting Wnt5a/NPC1 Signaling Pathway[J].Chinese Journal of Experimental Traditional Medical Formulae,2023,29(18):62-68. DOI： 10.13422/j.cnki.syfjx.20230936.

摘要

目的

探讨小檗碱（BBR）在防治小鼠动脉粥样硬化（AS）病变中对脂自噬的调节作用及分子机制。

方法

采用载脂蛋白E基因敲除（ApoE

-/-

）小鼠50只随机分为AS模型组、阿托伐他汀组（5 mg·kg

-1

）、BBR低、中、高剂量组（2.5、5、10 mg·kg

-1

）；另设10只C57BL/6J小鼠为空白组。12周后苏木素-伊红（HE）及油红O染色检测主动脉AS斑块病理学改变；生化检测血清脂质水平；酶联免疫吸附测定法（ELISA）检测血清炎症因子白细胞介素-6（IL-6）、肿瘤坏死因子-

（TNF-

）水平、氧化应激标记物活性氧（ROS）含量及血清脂自噬标记物Beclin1、微管相关蛋白1轻链3Ⅱ（LC3Ⅱ）水平；黄嘌呤氧化酶法检测血清超氧化物歧化酶（SOD）活力；免疫组化（IHC）检测主动脉无翅型MMTV整合位点家族成员5a（Wnt5a）、C1型尼曼-匹克蛋白（NPC1）分布；蛋白免疫印迹法（Western blot）检测主动脉Wnt5a、NPC1蛋白表达。

结果

与空白组比较，AS模型组小鼠可见显著的AS斑块形成，血清总胆固醇（TC）、甘油三酯（TG）、低密度脂蛋白胆固醇（LDL-C）、IL-6、TNF-

、ROS、主动脉Wnt5a分布及蛋白表达均显著升高（

0.01），血清高密度脂蛋白胆固醇（HDL-C）、SOD、Beclin1、LC3Ⅱ、主动脉NPC1分布及蛋白表达均显著降低（

0.01）；与AS模型组比较，阿托伐他汀组、BBR中剂量组及BBR高剂量小鼠AS斑块面积明显减少（

0.05，

0.01），血清TC、TG、LDL-C、IL-6、TNF-

、ROS、主动脉Wnt5a分布及蛋白表达均明显降低（

0.05，

0.01），血清HDL-C、SOD、Beclin1、LC3Ⅱ、主动脉NPC1分布及蛋白表达均明显升高（

0.05，

0.01）；与阿托伐他汀组比较，BBR中剂量组小鼠以上检测指标差异无统计学意义。

结论

BBR可通过竞争性结合Wnt5a激活NPC1表达，上调脂自噬水平降低血脂，抑制炎症介质的释放及氧化应激损伤从而发挥防治AS功效。

Abstract

Objective

To investigate the regulatory effect and molecular mechanism of berberine （BBR） on lipophagy in the prevention and treatment of atherosclerotic （AS） lesions in mice.

Method

Fifty apolipoprotein E-knockout （ApoE

-/-

） mice were randomly divided into an AS model group， an atorvastatin group （5 mg·kg

-1

）， and low-， medium-， and high-dose BBR groups （2.5， 5， 10 mg·kg

-1

）. Ten C57BL/6J mice were assigned to the control group. After 12 weeks， hematoxylin-eosin （HE） and oil red O staining were performed to assess the histopathological changes of AS plaques in the aorta. Biochemical analysis was used to measure serum lipid levels， and enzyme-linked immunosorbent assay （ELISA） was employed to measure the levels of inflammatory cytokines interleukin-6 （IL-6） and tumor necrosis factor-

（TNF-

）， oxidative stress marker reactive oxygen species （ROS）， and serum lipophagy marker Beclin1 and microtubule-associated protein 1 light chain 3 Ⅱ （LC3Ⅱ）. The xanthine oxidase method was used to measure serum superoxide dismutase （SOD） activity. Immunohistochemistry （IHC） was used to detect the distribution of wingless-type MMTV integration site family member 5a （Wnt5a） and Nieman Pick type C1 （NPC1） in the aorta， and Western blot was used to determine the protein expression of Wnt5a and NPC1 in the aorta.

Result

Compared with the control group， the AS model group showed significant AS plaque formation， significantly elevated levels of serum total cholesterol （TC）， triglycerides （TG）， low-density lipoprotein cholesterol （LDL-C）， IL-6， TNF-

， and ROS， aortic Wnt5a distribution and protein expression （

0.01）， and significantly reduced levels of serum high-density lipoprotein cholesterol （HDL-C）， SOD， Beclin1， LC3Ⅱ， and aortic NPC1 distribution and protein expression （

0.01）. Compared with the AS model group， the atorvastatin group， and high- and medium-dose BBR groups showed a significant reduction in AS plaque area （

0.05，

0.01）， significantly decreased levels of serum TC， TG， LDL-C， IL-6， TNF-

， ROS， and aortic Wnt5a distribution and protein expression （

0.05，

0.01）， and significantly increased levels of serum HDL-C， SOD， Beclin1， LC3Ⅱ， and aortic NPC1 distribution and protein expression （

0.05，

0.01）. There was no statistically significant difference in the above indicators between the atorvastatin group and the medium-dose BBR group.

Conclusion

BBR can competitively bind to Wnt5a to activate NPC1 expression， upregulate lipophagy levels， reduce blood lipids， and inhibit the release of inflammatory mediators and oxidative stress damage， thereby exerting a preventive and therapeutic effect on AS.

关键词

小檗碱脂自噬载脂蛋白E基因敲除小鼠无翅型MMTV整合位点家族成员5a（Wnt5a）/C1型尼曼-匹克蛋白（NPC1）信号通路

Keywords

berberinelipophagyapolipoprotein E-knockout micewingless-type MMTV integration site family member 5a （Wnt5a）/Nieman Pick type C1 （NPC1） signaling pathway

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