结合珠蛋白通过抑制ERK1/2减轻肝细胞铁死亡

doi:10.3969/j.issn.1674-8115.2021.08.002

上海交通大学学报(医学版) ›› 2021, Vol. 41 ›› Issue (8): 999-1008.doi: 10.3969/j.issn.1674-8115.2021.08.002

结合珠蛋白通过抑制ERK1/2减轻肝细胞铁死亡

魏倩¹(), 张颖婷¹, 林龙帅¹^,², 何恩俊², 何咏元¹, 苏滢泓¹, 段澄澄¹, 王斯源¹, 赵庆华², 赵倩¹^,³, 贺明¹()

^1.上海交通大学医学院病理生理学系，细胞分化与凋亡教育部重点实验室，上海 200025
^2.上海交通大学附属第一人民医院骨科，上海 201620
^3.上海交通大学应激与肿瘤创新单元（2019RU043），中国医学科学院，上海 200025

出版日期:2021-08-28 发布日期:2021-08-13
通讯作者: 贺明 E-mail:1102225683@qq.com;heming@shsmu.edu.cn
作者简介:魏倩（1998—），女，硕士生；电子信箱：1102225683@qq.com。
基金资助:
国家自然科学基金(82070603);上海市自然科学基金(19ZR1428400);上海交通大学医学院高水平地方高校创新团队(SSMU-ZDCX20180800);中央高校基本科研业务费专项资金资助，中国医学科学院医学与健康科技创新工程(2019-I2M-5-051);国家重点研发计划(2020YFA0803403);上海交通大学医学院青年科技创新工作室资助项目(JYKCGZS15)

Haptoglobin suppresses hepatocyte ferroptosis via inhibition of the ERK1/2 signaling pathway

Qian WEI¹(), Ying-ting ZHANG¹, Long-shuai LIN¹^,², En-jun HE², Yong-yuan HE¹, Ying-hong SU¹, Cheng-cheng DUAN¹, Si-yuan WANG¹, Qing-hua ZHAO², Qian ZHAO¹^,³, Ming HE¹()

^1.Department of Pathophysiology, Key Laboratory for Cell Differentiation and Apoptosis Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
^2.Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai 201620, China
^3.Shanghai Jiao Tong University, Research Units of Stress and Tumor (2019RU043), Chinese Academy of Medical Sciences, Shanghai 200025, China

Online:2021-08-28 Published:2021-08-13
Contact: Ming HE E-mail:1102225683@qq.com;heming@shsmu.edu.cn

摘要/Abstract

摘要：

目的·探究结合珠蛋白（haptoglobin，Hp）在肝细胞铁死亡（ferroptosis）中的作用及机制。方法·给予8周龄的C57BL/6J雄性小鼠正常饲料（normal iron diet，NID组，n=5）和高铁饲料（high iron diet，HID组，n=8）饲喂12周后，收集2组小鼠的肝脏和血清。利用血清学生化指标、肝脏苏木精-伊红（hematoxylin-eosin，H-E）染色、天狼星红染色、普鲁士蓝染色和4-羟基壬烯醛（4-hydroxynonenal，4-HNE）染色明确2组小鼠肝脏损伤、病理学改变、纤维化、铁沉积和脂质过氧化反应程度；利用RNA测序（RNA-sequencing，RNA-seq）技术和生物信息学分析高铁饮食对小鼠肝脏转录组表达的调控，并筛选新的调控铁死亡的候选基因。在AML-12小鼠肝细胞中过表达Hp或利用siRNA敲减Hp后，给予铁死亡诱导剂RAS合成致死分子3 （RAS-selective lethal small molecule 3，RSL3）和/或细胞外信号调节激酶1/2 （extracellular regulated protein kinases 1/2，ERK1/2）活性抑制剂SCH772984，利用细胞计数、real-time PCR和C11-BODIPY^581/591免疫荧光及流式细胞术等实验明确Hp在肝细胞铁死亡中的作用及机制。结果·相较于NID组小鼠，HID组小鼠血清中谷丙转氨酶（glutamic-pyruvic transaminase，GPT）和谷草转氨酶（glutamic-oxalacetic transaminase，GOT）水平明显升高，肝脏出现明显的肝细胞死亡、纤维化、铁沉积和脂质过氧化产物累积。RNA-seq及生物信息学分析结果分析发现，HID组小鼠肝脏中急性期反应、氧化还原反应、催化反应及血红蛋白结合等信号通路发生了明显的变化，而Hp mRNA在HID组显著下调。而且，HID组小鼠肝组织及RSL3处理的AML-12肝细胞中的Hp mRNA和蛋白表达水平均明显降低。重要的是，在AML-12肝细胞中，Hp过表达可明显减轻RSL3引起的肝细胞脂质过氧化和铁死亡。反之，Hp敲减可加重RSL3引起的肝细胞铁死亡。机制上，Hp明显抑制RSL3引起的肝细胞ERK1/2磷酸化的增强；而且，SCH772984可明显恢复Hp敲减导致的肝细胞脂质过氧化和铁死亡的加重。结论·Hp是一种新的肝细胞铁死亡抑制分子，而且Hp主要通过抑制ERK1/2活性减轻肝细胞铁死亡及其引起的肝损伤。

关键词: 结合珠蛋白, 肝细胞, 铁死亡, 脂质过氧化, 细胞外信号调节激酶1/2

Abstract:

Objective·To explore the role and mechanism of haptoglobin (Hp) in hepatocyte ferroptosis.

Methods·Thirteen 8-week-old C57BL/6J male mice were randomly divided into two groups: one group of mice were fed with normal iron diet (NID group, n=5) and the other were fed with high iron diet (HID group, n=8). After 12 weeks, the murine serums and livers were collected from both groups. Liver injury, histopathological changes, hepatic fibrosis, iron deposition and peroxidation in murine liver tissues were determined by serum index test, hematoxylin-eosin (H-E) staining, Sirius red staining, Prussian blue staining and 4-hydroxynonenal (4-HNE) staining, respectively. RNA-sequencing (RNA-seq) and bioinformatics were used to analyze the effect of high iron diet on the expression of transcriptome in the murine livers and to screen new candidate genes that might regulate ferroptosis. After Hp was overexpressed or knocked down in mouse liver cells (AML-12), RAS-selective lethal small molecule 3 (RSL3) or/and extracellular regulated protein kinases 1/2 (ERK1/2) inhibitor SCH772984 was/were added to cells. The role and mechanism of Hp in hepatocyte ferroptosis were determined by cell counting, real-time PCR, C11-BODIPY^581/591 immunofluorescence and flow cytometry.

Results·After 12 weeks of feeding, the levels of glutamic-pyruvic transaminase (GPT) and glutamic-oxalacetic transaminase (GOT) in the HID group significantly increased compared with the NID group. The high iron diet induced hepatocytes death, hepatic fibrosis, iron deposition and lipid peroxidation products accumulation. RNA-seq analysis and bioinformatics results showed that acute phase response, catalytic activity response, antioxidant activity and hemoglobin binding signaling pathways were significantly regulated in the livers of HID mice, and Hp mRNA decreased significantly. Furthermore, the mRNA and protein expression levels of Hp in liver tissues of HID mice and in AML-12 hepatocytes treated with RSL3 obviously decreased. Importantly, Hp significantly alleviated lipid peroxidation and ferroptosis induced by RSL3 in AML-12 hepatocytes. Meanwhile, Hp suppressed RSL3-induced phosphorylation of ERK1/2 in AML-12 hepatocytes. Moreover, ERK1/2 inhibitor SCH772984 totally reversed the aggravation of hepatocyte ferroptosis induced by Hp knockdown.

Conclusion·Hp is a novel inhibitory molecule in hepatocytes ferroptosis, which alleviates hepatocyte ferroptosis and liver injury by inhibiting ERK1/2 signaling pathway.

Key words: haptoglobin (Hp), hepatocyte, ferroptosis, lipid peroxidation, extracellular regulated protein kinases1/2 (ERK1/2)

中图分类号:

R575.5

魏倩, 张颖婷, 林龙帅, 何恩俊, 何咏元, 苏滢泓, 段澄澄, 王斯源, 赵庆华, 赵倩, 贺明. 结合珠蛋白通过抑制ERK1/2减轻肝细胞铁死亡[J]. 上海交通大学学报(医学版), 2021, 41(8): 999-1008.

Qian WEI, Ying-ting ZHANG, Long-shuai LIN, En-jun HE, Yong-yuan HE, Ying-hong SU, Cheng-cheng DUAN, Si-yuan WANG, Qing-hua ZHAO, Qian ZHAO, Ming HE. Haptoglobin suppresses hepatocyte ferroptosis via inhibition of the ERK1/2 signaling pathway[J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2021, 41(8): 999-1008.

图/表 7

表1 Real-time PCR引物序列

Tab 1 Primer sequences for realtime-PCR

Gene	Forward primer sequence	Reverse primer sequence
Rpl13a	GAGGTCGGGTGGAAGTACCA	TGCATCTTGGCCTTTTCCTT
Hp	GCTATGTGGAGCACTTGGTTC	CACCCATTGCTTCTCGTCGTT
GPX4	GCAATGAGGCAAAACTGACG	CTTGATTACTTCCTGGCTCCTG
PTGS2	TGGCTGGAAAGATGGAGACAA	AAAGCTCTCTCTTGCATCACTG
ACSL4	CTCACCATTATATTGCTGCCTGT	TCTCTTTGCCATAGCGTTTTTCT

表2 所用siRNA序列

Tab 2 Sequences of siRNA

siRNA	Forward primer sequence	Reverse primer sequence
si-NC	UUCUCCGAACGUGUCACGUTT	ACGUGACACGUUCGGAGAATT
si-Hp	GGAGCACUUGGUUCGCUAUTT	AUAGCGAACCAAGUGCUCCTT

图1 高铁饮食诱导小鼠发生肝细胞铁死亡和肝损伤Note：A. Gross livers from C57BL/6J mice were fed on normal iron diet (NID, n=5) or high iron diet (HID, n=8) for 12 weeks (bar=5 mm). B. Murine liver weight/body weight. C/D. Representative images of murine liver tissues stained with H-E staining (C) and Sirius red staining (D) (bar=50 μm). E/F. Mouse serum GPT (E) and GOT (F) levels. G. Representative images of murine livers stained with Prussian blue staining (bar=50 μm). H. Hepatic iron content. I. Immunohistochemistry analysis of 4-HNE of murine liver (bar=50 μm). J. Hepatic MDA content. K?M. mRNA levels of PTGS2 (K), ACSL4 (L) and GPX4 (M) in murine livers measured by real-time PCR. Data were from 3 independent experiments, compared by using Student's t test. ①P=0.019, ②P=0.000, ③P=0.025, ④P=0.036, ⑤P=0.003.

Fig 1 High iron diet-induced hepatocyte ferroptosis and liver injury in mice

图2 高铁饮食引起的小鼠肝脏中转录组的表达变化Note：A/B. Heat maps demonstrating high iron diet-downregulated (A) or upregulated (B) mRNAs. Green and red colors indicate high and low gene expression, respectively. C. Gene ontology processes of molecular function. The top rank ordered processes, maps and networks are based on statistical significance.

Fig 2 Dysregulated mRNAs in livers of mice fed with high iron diet

图3 高铁饮食和RSL3抑制肝细胞Hp的mRNA和蛋白表达Note：A. GSEA analysis of the regulated mRNA in NID or HID mice. B. Heat map demonstrates deregulated mRNAs in GSEA analysis of acute phase response; green and red colors indicate high and low gene expression, respectively. C. Protein expression level of Hp in murine livers. D. mRNA level of Hp in murine livers. E. Hp protein expression level of AML-12 cells treated with RSL3. F. mRNA level of Hp in AML-12 cells treated with RSL3. Data were from 3 independent experiments, compared by using Student's t test. ①P=0.000. Ctrl—control.

Fig 3 High iron diet and RSL3 inhibiting the expression of Hp mRNA and protein in hepatocytes

图4 Hp过表达抑制RSL3诱导的肝细胞铁死亡Note：A/B. The mRNA (A) and protein (B) expression level of Hp in AML-12 cells overexpressing Hp and stimulated by 5 μmol/mL RSL3. C. The cell number of AML-12 cells overexpressing Hp and stimulated by 5 μmol/mL RSL3. D/E. The mRNA expression level of PTGS2 (D) and GPX4 (E) in AML-12 cells overexpressing Hp and stimulated by 5 μmol/mL RSL3. F. The lipid ROS level in AML-12 assessed by flow cytometry using C11-BODIPY581/591. G. Fluorescent microscope images of C11-BODIPY581/591 (bar=25 μm). Data were from 3 independent experiments, compared by using Student's t test. ①P=0.002,②P=0.009,③P=0.035,④P=0.016,⑤P=0.008, ⑥P=0.032,⑦P=0.019,⑧P=0.000,⑨P=0.004. Hp-OE—overexpression of Hp.

Fig 4 Hp overexpression inhibiting hepatocyte ferroptosis induced by RSL3

图5 Hp通过抑制ERK1/2磷酸化减轻肝细胞铁死亡Note：A. The phosphorylation and protein expression of ERK1/2 in AML-12 cells. B/D?F. The mRNA levels of Hp (B), PTGS2 (D), ACSL4 (E) and GPX4 (F) in AML-12 cells overexpressing Hp and stimulated by 5 μmol/mL RSL3 and/or 5 μmol/mL SCH772984. C. The cell number of AML-12 cells. G. The lipid ROS level of AML-12 cells overexpressing Hp and stimulated by 5 μmol/mL RSL3 and/or 5 μmol/mL SCH772984 assessed by flow cytometry using C11-BODIPY581/591. H. Quantitative result of figure G. Data were from 3 independent experiments, compared by using Student's t test. ①P=0.001, ②P=0.006, ③P=0.000, ④P=0.046, ⑤P=0.028, ⑥P=0.032, ⑦P=0.045, ⑧P=0.014, ⑨P=0.009, ⑩P=0.007. si-Hp—Hp knockdown.

Fig 5 Hp suppressed hepatocyte ferroptosis by inhibiting ERK1/2 phosphorylation

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结合珠蛋白通过抑制ERK1/2减轻肝细胞铁死亡

Haptoglobin suppresses hepatocyte ferroptosis via inhibition of the ERK1/2 signaling pathway

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