化橘红配方颗粒通过维持铁稳态并抑制脂质过氧化和铁死亡缓解斑马鱼脂肪性肝病

doi:10.12122/j.issn.1673-4254.2024.12.01

南方医科大学学报 ›› 2024, Vol. 44 ›› Issue (12): 2265-2275.doi: 10.12122/j.issn.1673-4254.2024.12.01

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化橘红配方颗粒通过维持铁稳态并抑制脂质过氧化和铁死亡缓解斑马鱼脂肪性肝病

张榆雪¹(), 蓝洁莹¹, 马昕怡², 周琼¹, 秦梦晨¹, 高磊¹^,³^,⁴()

^1.南方医科大学，中医药学院，广东广州 510515
^2.南方医科大学，第一临床医学院，广东广州 510515
^3.广东省中药制剂重点实验室，广东广州 510515
^4.广东省中西医结合防治情志病基础研究卓越中心，广东广州 510515

收稿日期:2024-08-21 出版日期:2024-12-20 发布日期:2024-12-26
通讯作者: 高磊 E-mail:1610045163@qq.com;rayg@foxmail.com
作者简介:张榆雪，在读硕士研究生，E-mail: 1610045163@qq.com
基金资助:
国家自然科学基金(82074131);广东省基础与应用基础研究基金(2022A1515220179)

Exocarpium Citri Grandis formula granules alleviate fatty liver disease in Zebrafish by maintaining iron homeostasis and suppressing lipid peroxidation and ferroptosis

Yuxue ZAHNG¹(), Jieying LAN¹, Xinyi MA², Qiong ZHOU¹, Mengchen QIN¹, Lei GAO¹^,³^,⁴()

^1.School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
^2.the First Clinical School of Medicine, Southern Medical University, Guangzhou 510515, China
^3.GuangDongProvicial Key Laboratory of Chinese Medicine Pharmaceutics, Guangzhou 510515, China
^4.Guangdong Province Integrated Traditional Chinese and Western Medicine Prevention and Treatment of emotional disease basic research excellence center, Guangzhou 510515

Received:2024-08-21 Online:2024-12-20 Published:2024-12-26
Contact: Lei GAO E-mail:1610045163@qq.com;rayg@foxmail.com
Supported by:
National Natural Science Foundation of China(82074131)

摘要/Abstract

摘要：

目的探讨化橘红配方颗粒治疗脂肪性肝病（FLD）的药效作用和具体机制。方法将受精后3 d的斑马鱼幼鱼随机分为空白组、模型对照组、化橘红配方颗粒处理组（16、32、64 μg/mL），分别构建斑马鱼幼鱼非酒精性脂肪肝（NAFLD）和酒精性脂肪肝（ALD）模型，采用生存分析、病理组织切片、全鱼油红O染色和实时定量荧光PCR实验评价化橘红配方颗粒治疗FLD的药效，并从CAV1和铁代谢及铁死亡角度探讨其治疗FLD的具体机制，通过普鲁士蓝染色、DCFH-DA活体探针、丙二醛含量检测、实时定量荧光PCR实验和CAV1免疫组织化学染色分析化橘红配方颗粒治疗FLD的药效验证和具体机制。结果化橘红配方颗粒能减轻斑马鱼幼鱼NAFLD和ALD模型中的脂质累积，减少脂肪酸合成酶、固醇调节元件结合蛋白1、3-羟基-3-甲基戊二酰辅酶A还原酶、肿瘤坏死因子-α和白介素6的表达水平，升高载脂蛋白A1和PPARα表达水平。化橘红配方颗粒可以减少斑马鱼幼鱼NAFLD和ALD模型中肝脏的铁沉积，减少幼鱼体内的丙二醛和活性氧含量（P<0.05）。NAFLD状态下，不同浓度的化橘红配方颗粒可升高Tf、TfR、FPN和SLC7A11表达（P<0.05），中、高浓度的化橘红配方颗粒可升高谷胱甘肽过氧化物酶4（GPX4）的表达（P<0.05）；ALD状态下，斑马鱼幼鱼的Tf、TfR和FPN表达升高，不同浓度的化橘红配方颗粒可降低这些基因的表达（P<0.05）。化橘红配方颗粒对ALD状态下SLC7A11的表达无明显影响，但高浓度的化橘红配方颗粒可升高GPX4的表达（P<0.05），免疫组织化学染色和实时定量荧光PCR实验结果显示，在NAFLD和ALD状态下，斑马鱼幼鱼肝脏的CAV1升高，而中、高浓度的化橘红配方颗粒可明显改善评价两种脂肪肝状态下斑马鱼幼鱼肝脏的CAV1表达。结论化橘红配方颗粒可减轻NAFLD和ALD的脂质累积和炎症反应，并通过减少CAV1的表达纠正NAFLD和ALD的铁稳态失衡、脂质过氧化和铁死亡。

关键词: 脂肪性肝病, 化橘红, 配方颗粒, 斑马鱼, 铁死亡

Abstract:

Objective To investigate the therapeutic effect of Exocarpium Citri Grandis formula granules (ECGFG) on fatty liver disease (FLD) in zebrafish and explore the underlying mechanism. Methods Nonalcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (ALD) models were established in zebrafish larvae at 3 days post fertilization (dpf), in which the treatment efficacy of 16, 32, or 64 μg/mL ECGFG was evaluated by examining zebrafish survival and liver pathologies and using whole-fish oil red O staining and RT-qPCR. The therapeutic mechanism of ECGFG for FLD was investigated using Prussian blue staining, DCFH-DA probe, MDA content detection, RT-qPCR assay and immunohistochemical staining for CAV1. Results In zebrafish models of NAFLD and ALD, treatment with ECGFG significantly reduced lipid accumulation and the expression levels of FASN, SREBP1, HMGCRA, TNF-α and IL-6, increased the expressions of Apoa1 and PPARα, and reduced iron deposition and the contents of MDA and ROS in the liver. In zebrafish models of NAFLD, treatment with ECGFG at the 3 doses significantly increased hepatic expressions of Tf, TfR, FPN and SLC7A11, and at the doses of 32 and 64 μg/mL, ECGFG obviously increased hepatic expression of GPX4. ALD fish models showed significantly increased hepatic expressions of Tf, TfR and FPN, which were effectively lowered by treatment with ECGFG at the 3 doses. ECGFG did not obviously affect the expression of SLC7A11, but its high dose (64 μg/mL) caused significant elevation of GPX4 expression. Both zebrafish models of NAFLD and ALD showed obviously increased CAV1 expression level in the liver, which was significantly reduced by treatment with 32 and 64 μg/mL ECGFG. Conclusion In zebrafish models of NAFLD and ALD, ECGFG can alleviate lipid accumulation and inflammatory response and lower the expression level of CAV1 to restore iron homeostasis and suppress lipid peroxidation and ferroptosis in the liver.

Key words: fatty liver disease, Exocarpium Citri Grandis, formula granules, zebrafish, iron homeostasis

张榆雪, 蓝洁莹, 马昕怡, 周琼, 秦梦晨, 高磊. 化橘红配方颗粒通过维持铁稳态并抑制脂质过氧化和铁死亡缓解斑马鱼脂肪性肝病[J]. 南方医科大学学报, 2024, 44(12): 2265-2275.

Yuxue ZAHNG, Jieying LAN, Xinyi MA, Qiong ZHOU, Mengchen QIN, Lei GAO. Exocarpium Citri Grandis formula granules alleviate fatty liver disease in Zebrafish by maintaining iron homeostasis and suppressing lipid peroxidation and ferroptosis[J]. Journal of Southern Medical University, 2024, 44(12): 2265-2275.

图/表 7

表1 引物序列

Tab.1 Primer sequences for RT-qPCR

Primer	Primer sequence (5'-3')	Primer sequence (5'-3')
β-actin	ATGGATGAGGAAATCGCTGCC	CTCCCTGATGTCTGGGTCGTC
FASN	GAGAAAGCTTGCCAAACAGG	GAGGGTCTTGCAGGAGACAG
SREBP1	CATCCACATGGCTCTGAGTG	CTCATCCACAAAGAAGCGGT
HMGCRA	CCTGTTAGCCGTCAGTGGA	TCTTTGACCACTCGTGCCG
PPARα	TGCTGGACTACCAGAACTGTGACA	TGCTGGCTGAGAACACTTCTGAG
Apoa1	GCACTAAGCTGACCGAGCGT	GGAGGTCCTGGGTGTGTGGA
TNF-α	GCTTATGAGCCATGCAGTGA	TGCCCAGTCTGTCTCCTTCT
IL6	CCTCAAACCTTCAGACCGCT	GAACAGGATCGAGTGGACCG
Tf	GTTGATGGTGGCCAGGTGTA	AGCGTAGTAACTTGCGGTCC
TfR	CCGCTCATACTCGCGGTTTA	TGGTTCAGAACGACCTGTGG
FPN	GCCAACGTCACCGTTTTTGA	CGGTCAAGTCGAAGGACCAA
GPX4	GAGGTTTACGCATCCTGGCT	GGCTGATCCTTCAGCCACTT
SLC7A11	TGTGGGAATGTCACTGGTGG	ACGCCTCCAGAATGTACGTG

图1 化橘红配方颗粒的斑马鱼急性毒性实验结果

Fig.1 Results of acute toxicity test of Exocarpium Citri Grandis (ECG) in zebrafish larvae. A: Development of zebrafish larvae 96 h after ECG administration. B: Effects of ECG granules on survival of zebrafish. C: Effects of ECG granules on heart rate of zebrafish at 96 h after administration.

图2 化橘红配方颗粒治疗非酒精性脂肪肝的药效评价

Fig.2 Efficacy evaluation of ECG decoction tablets and ECG granules for treatment of NAFLD in zebrafish larvae. A: HE staining of the liver of zebrafish larvae in each group. B: Whole fish oil red O staining in different groups. C: Effects of ECG decoction tablets and ECG granules on lipid metabolism-related genes and inflammatory factors. ECGFG:Exocarpium Citri Grandis formula granules.*P<0.05, **P<0.01, ***P<0.001, ****P<0.0001.

图3 化橘红配方颗粒治疗酒精性脂肪肝的药效评价

Fig.3 Efficacy evaluation of ECG decoction tablets and ECG granules for treatment of ALD in zebrafish larvae. A: HE staining of the liver of zebrafish larvae in each group. B: Whole fish oil red O staining in different groups. C: Effects of ECG decoction tablets and ECG granules on lipid metabolism-related genes and inflammatory factors. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001.

图4 化橘红配方颗粒对非酒精性脂肪肝铁代谢和铁死亡的作用评估

Fig.4 Effect of ECG granules on iron metabolism and ferroptosis in zebrafish larvae models of NAFLD. A: Prussian blue staining of the liver of zebrafish larvae in each group. B: DCFH-DA probe detection of zebrafish larvae in each group. C: Detection of MDA content in zebrafish larvae in each group. D: Effects of ECG granules on iron metabolism- and ferroptosis-related genes. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001.

图5 化橘红配方颗粒对酒精性脂肪肝铁代谢和铁死亡的作用评估

Fig.5 Effect of ECG granules on iron metabolism and ferroptosis in zebrafish larvae models of ALD. A: Prussian blue staining of the liver of zebrafish larvae in each group. B: DCFH-DA probe detection of zebrafish larvae in each group. C: Detection of MDA content in zebrafish larvae in each group. D: Effects of ECG granules on expressions of iron metabolism- and ferroptosis-related genes. ***P<0.001, ****P<0.0001.

图6 化橘红配方颗粒可能通过CAV1调控肝铁代谢和铁死亡

Fig.6 ECG granules regulate hepatic iron metabolism and ferroptosis possibly through CAV1 in zebrafish larvae. A: Liver CAV1 immunohistochemical staining in zebrafish larvae models of NAFLD. B: Effect of ECG granules on CAV1 expression in zebrafish larvae models of NAFLD. C: Liver CAV1 immunohistochemical staining in zebrafish larvae models of ALD. D: Effect of ECG granules on CAV1 expression in zebrafish larvae models of ALD. ****P<0.0001.

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化橘红配方颗粒通过维持铁稳态并抑制脂质过氧化和铁死亡缓解斑马鱼脂肪性肝病

Exocarpium Citri Grandis formula granules alleviate fatty liver disease in Zebrafish by maintaining iron homeostasis and suppressing lipid peroxidation and ferroptosis

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