微小RNA-377-3p调控自噬改善脂多糖/D-半乳糖胺诱导的急性肝衰竭的机制研究

doi:10.3877/cma.j.issn.1674-6880.2023.02.001

目的

本研究旨在研究微小RNA-377-3p（miR-377-3p）通过成纤维细胞生长因子受体1（FGFR1）对急性肝衰竭（ALF）自噬和凋亡的影响。

方法

分别通过D-半乳糖胺（D-GalN）/脂多糖（LPS）和D-GalN/肿瘤坏死因子α（TNF-α）诱导ALF动物模型和细胞凋亡模型。将12只C57BL/6J小鼠分为对照组和模型组，每组6只。将细胞分为对照组、模型组（经D-GalN、TNF-α诱导）、NC mimic组（D-GalN、TNF-α诱导并转染无意义miRNA对照序列）、miR-377-3p mimic组（D-GalN、TNF-α诱导并转染miR-377-3p模拟物）和miR-377-3p mimic + 3-MA组（D-GalN、TNF-α诱导并转染miR-377-3p模拟物的同时应用自噬抑制剂3-MA干预）。检测小鼠肝脏组织病理情况、血清中生化参数水平、凋亡相关蛋白、自噬相关蛋白以及各组细胞中miR-377-3p RNA、自噬相关蛋白、FGFR1蛋白表达水平。通过双荧光素酶报告基因实验检测miR-377-3p和FGFR1靶向结合关系，并采用流式细胞术检测细胞凋亡情况。

结果

苏木素-伊红（HE）染色结果显示，对照组小鼠中央静脉周围肝细胞呈放射状排列，无炎症细胞浸润；模型组小鼠中肝小叶结构破坏，大量肝细胞坏死，周围炎症细胞浸润。5组细胞的凋亡率和自噬蛋白Beclin-1、LC3Ⅱ/Ⅰ、p62的表达比较，差异均有统计学意义（F = 88.520、42.760、95.870、62.930，P均< 0.001），且miR-377-3p mimic组细胞凋亡率和p62蛋白水平均较模型组显著降低，Beclin-1、LC3Ⅱ/Ⅰ水平则均显著升高（P均< 0.05）。对照组、模型组、NC mimic组、miR-377-3p mimic组FGFR1蛋白表达水平比较，差异具有统计学意义（F = 84.670，P < 0.001），且miR-377-3p mimic组FGFR1表达水平较模型组显著降低（P < 0.05）。对照组、模型组、miR-377-3p mimic组、miR-377-3p mimic + NC组（D-GalN、TNF-α诱导并转染miR-377-3p模拟物和空白载体）和miR-377-3p mimic + FGFR1组（D-GalN、TNF-α诱导并转染miR-377-3p模拟物和FGFR1目的序列载体）自噬相关蛋白Beclin-1、LC3Ⅱ/Ⅰ和p62的表达水平比较，差异均有统计学意义（F = 63.840、61.590、127.800，P均< 0.001），且miR-377-3p mimic + FGFR1组较miR-377-3p mimic组LC3Ⅱ/Ⅰ、Beclin-1水平均降低，p62蛋白水平升高（P均< 0.05）。

结论

miR-377-3p靶向负调控FGFR1的表达，增强L02细胞自噬水平减轻D-GalN/TNF-α诱导的细胞凋亡，发挥ALF的保护作用。

关键词: 微小RNA-377-3p, 成纤维细胞生长因子受体, 自噬, 急性肝衰竭

Objective

To explore the effect of microRNA-377-3p (miR-377-3p) on autophagy and apoptosis in acute liver failure (ALF) through fibroblast growth factor receptor 1 (FGFR1).

Methods

D-galactosamine (D-GalN)/lipopolysaccharide and D-GalN/tumor necrosis factor-alpha (TNF-α) were respectively used to induce ALF animal models and cell apoptosis models. Twelve C57BL/6J mice were divided into a control group and a model group, with six mice in each group. Cells were divided into a control group, a model group (induced by D-GalN and TNF-α), a NC mimic group (induced by D-GalN and TNF-α and transfected with nonsense miRNA control sequence), a miR-377-3p mimic group (induced by D-GalN and TNF-α and transfected with miR-377-3p mimics) and a miR-377-3p mimic + 3-MA group (induced by D-GalN and TNF-α and transfected with miR-377-3p mimics while applying autophagy inhibitor 3-MA intervention). The pathology of liver tissue, the serum levels of biochemical parameters, apoptosis-related proteins, autophagy-related proteins and the cellular expression levels of miR-377-3p RNA, autophagy-related proteins, FGFR1 protein were examined in each group. The targeted binding relationship between miR-377-3p and FGFR1 was measured by dual-luciferase reporter gene experiment and apoptosis was determined by flow cytometry.

Results

Hematoxylin-eosin staining showed that the hepatocytes around the central vein of the control group were arranged radially, and there was no inflammatory cell infiltration. In the model group, the structure of hepatic lobule was destroyed, a large number of liver cells were necrotic, and surrounding inflammatory cells were infiltrated. There were significant differences in the apoptosis rate and expressions of autophagy proteins Beclin-1, LC3Ⅱ/Ⅰ and p62 in the five groups (F = 88.520, 42.760, 95.870, 62.930; all P < 0.001). Compared with the model group, the apoptosis rate and p62 protein level of the miR-377-3p mimic group were significantly decreased, while the levels of Beclin-1 and LC3Ⅱ/Ⅰ were significantly increased (all P < 0.05). The FGFR1 protein expression levels were significantly different in the control group, model group, NC mimic group and miR-377-3p mimic group (F = 84.670, P < 0.001). The FGFR1 expression level in the miR-377-3p mimic group was significantly decreased compared with the model group (P < 0.05). There were statistically significant differences in the expression levels of autophagy related proteins Beclin-1, LC3Ⅱ/Ⅰ and p62 in the control group, model group, miR-377-3p mimic group, miR-377-3p mimic + NC group (induced by D-GalN and TNF-α and transfected with miR-377-3p mimics and blank vectors) and miR-377-3p mimic + FGFR1 group (induced by D-GalN and TNF-α and transfected with miR-377-3p mimics and FGFR1 target sequence vectors) (F = 63.840, 61.590, 127.800; all P < 0.001). Compared with the miR-377-3p mimic group, Beclin-1 and LC3Ⅱ/Ⅰ levels in the miR-377-3p mimic + FGFR1 group were decreased, while p62 protein levels were increased (all P < 0.05).

Conclusion

MiR-377-3p negatively regulates the FGFR1 expression and enhances the autophagy level in L02 cells to reduce the apoptosis induced by D-GalN/TNF-α and exert the protective effect for ALF.

Key words: MicroRNA-377-3p, Fibroblast growth factor receptor 1, Autophagy, Acute liver failure

图1 LPS/D-GalN诱导的ALF模型构建成功注：LPS.脂多糖；D-GalN. D-半乳糖胺；ALF.急性肝衰竭；ALT.丙氨酸转氨酶；AST.天冬氨酸氨基转移酶；Bcl-2. B淋巴细胞瘤2基因；GAPDH.甘油醛-3-磷酸脱氢酶；HE.苏木素-伊红；a ~ b图为肝脏组织病理情况，结果显示对照组（a图）小鼠中央静脉周围肝细胞呈放射状排列整齐，无炎症细胞浸润；模型组（b图）小鼠中肝小叶结构破坏，大量肝细胞坏死，周围炎症细胞浸润（HE染色　× 200）；c ~ d图为ALT和AST活性用于评估肝脏功能，与对照组比较，^aP < 0.05；e图为Western-blotting检测肝脏组织中凋亡相关蛋白水平

表1 两组小鼠间凋亡相关蛋白相对灰度值的比较（ ± s）

组别	只数	Bcl-2	Bax	Cleaved caspase-3	Pro caspase-3
对照组	6	1.000 ± 0.112	1.00 ± 0.06	1.00 ± 0.13	1.00 ± 0.09
模型组	6	0.190 ± 0.020	4.99 ± 0.59	9.37 ± 0.73	1.04 ± 0.12
t值		17.460	16.510	27.540	0.617
P值		< 0.001	< 0.001	< 0.001	0.551

表1 两组小鼠间凋亡相关蛋白相对灰度值的比较（ ± s）

组别	只数	Bcl-2	Bax	Cleaved caspase-3	Pro caspase-3
对照组	6	1.000 ± 0.112	1.00 ± 0.06	1.00 ± 0.13	1.00 ± 0.09
模型组	6	0.190 ± 0.020	4.99 ± 0.59	9.37 ± 0.73	1.04 ± 0.12
t值		17.460	16.510	27.540	0.617
P值		< 0.001	< 0.001	< 0.001	0.551

图2 LPS/D-GalN诱导的ALF小鼠模型中miR-377-3p低表达和自噬水平降低注：LPS.脂多糖；D-GalN. D-半乳糖胺；ALF.急性肝衰竭；miR-377-3p.微小RNA-377-3p；GAPDH.甘油醛-3-磷酸脱氢酶；qRT-PCR.实时荧光定量PCR；a图为Western-blotting检测肝脏组织中自噬相关蛋白水平；b图为qRT-PCR检测肝脏组织中miR-377-3p相对表达水平，与对照组比较，^aP < 0.05

表2 两组小鼠间自噬相关蛋白相对灰度值的比较（ ± s）

组别	只数	Beclin-1	LC3Ⅱ/Ⅰ	p62
对照组	6	1.00 ± 0.05	1.00 ± 0.08	1.00 ± 0.10
模型组	6	0.49 ± 0.05	0.49 ± 0.07	2.44 ± 0.10
t值		17.190	11.790	25.580
P值		< 0.001	< 0.001	< 0.001

表2 两组小鼠间自噬相关蛋白相对灰度值的比较（ ± s）

组别	只数	Beclin-1	LC3Ⅱ/Ⅰ	p62
对照组	6	1.00 ± 0.05	1.00 ± 0.08	1.00 ± 0.10
模型组	6	0.49 ± 0.05	0.49 ± 0.07	2.44 ± 0.10
t值		17.190	11.790	25.580
P值		< 0.001	< 0.001	< 0.001

图3 miR-377-3p通过增强L02细胞自噬水平减轻D-GalN/TNF-α诱导的细胞凋亡注：miR-377-3p.微小RNA-377-3p；D-GalN. D-半乳糖胺；TNF-α.肿瘤坏死因子α；GAPDH.甘油醛-3-磷酸脱氢酶；FITC.异硫氰酸荧光素；qRT-PCR.实时荧光定量PCR；a图为Western-blotting检测细胞中自噬相关蛋白水平；b图为qRT-PCR检测细胞中miR-377-3p相对表达水平，与NC mimic组比较，^aP < 0.05；c图为流式细胞术检测细胞凋亡情况

表3 各组细胞凋亡率、自噬相关蛋白相对灰度值的比较（ ± s）

组别	样本数	细胞凋亡率（%）	Beclin-1	LC3Ⅱ/Ⅰ	p62
对照组	3	4.4 ± 0.6	1.00 ± 0.04	1.00 ± 0.11	1.00 ± 0.10
模型组	3	21.6 ± 0.8^a	0.47 ± 0.08^a	0.28 ± 0.06^a	2.07 ± 0.14^a
NC mimic组	3	23.6 ± 1.8	0.49 ± 0.08	0.28 ± 0.06	2.12 ± 0.11
miR-377-3p mimic组	3	11.3 ± 1.7^b	1.03 ± 0.09^b	1.04 ± 0.07^b	1.07 ± 0.05^b
miR-377-3p mimic + 3-MA组	3	15.9 ± 1.8^c	0.47 ± 0.09^c	0.26 ± 0.05^c	2.17 ± 0.21^c
F值		88.520	42.760	95.870	62.930
P值		< 0.001	< 0.001	< 0.001	< 0.001

表3 各组细胞凋亡率、自噬相关蛋白相对灰度值的比较（ ± s）

组别	样本数	细胞凋亡率（%）	Beclin-1	LC3Ⅱ/Ⅰ	p62
对照组	3	4.4 ± 0.6	1.00 ± 0.04	1.00 ± 0.11	1.00 ± 0.10
模型组	3	21.6 ± 0.8^a	0.47 ± 0.08^a	0.28 ± 0.06^a	2.07 ± 0.14^a
NC mimic组	3	23.6 ± 1.8	0.49 ± 0.08	0.28 ± 0.06	2.12 ± 0.11
miR-377-3p mimic组	3	11.3 ± 1.7^b	1.03 ± 0.09^b	1.04 ± 0.07^b	1.07 ± 0.05^b
miR-377-3p mimic + 3-MA组	3	15.9 ± 1.8^c	0.47 ± 0.09^c	0.26 ± 0.05^c	2.17 ± 0.21^c
F值		88.520	42.760	95.870	62.930
P值		< 0.001	< 0.001	< 0.001	< 0.001

图4 miR-377-3p靶向负调控D-GalN/TNF-α处理的L02细胞中FGFR1的表达注：miR-377-3p.微小RNA-377-3p；D-GalN. D-半乳糖胺；TNF-α.肿瘤坏死因子α；FGFR1.成纤维细胞生长因子受体1；GAPDH.甘油醛-3-磷酸脱氢酶；3' UTR. 3'非翻译区；a图为通过TargetScan软件预测FGFR1和miR-377-3p之间的结合位点；b图为FGFR1和miR-377-3p之间的相互作用通过L02细胞中的双荧光素酶报告基因测定证实，其中FGFR1-WT为插入野生型FGFR1基因3' UTR序列的荧光素酶报告基因质粒，FGFR1-MUT为插入FGFR1基因3'UTR序列突变后的荧光素酶报告基因质粒，与NC mimic组比较，^aP < 0.05；c图为Western-blotting检测细胞中FGFR1表达水平

表4 各组细胞FGFR1蛋白相对灰度值的比较（ ± s）

组别	样本数	FGFR1
对照组	3	1.00 ± 0.13
模型组	3	3.17 ± 0.25^a
NC mimic组	3	3.04 ± 0.34
miR-377-3p mimic组	3	1.14 ± 0.08^b
F值		84.670
P值		< 0.001

表4 各组细胞FGFR1蛋白相对灰度值的比较（ ± s）

组别	样本数	FGFR1
对照组	3	1.00 ± 0.13
模型组	3	3.17 ± 0.25^a
NC mimic组	3	3.04 ± 0.34
miR-377-3p mimic组	3	1.14 ± 0.08^b
F值		84.670
P值		< 0.001

图5 miR-377-3p靶向FGFR1调控D-GalN/TNF-α处理的L02细胞的自噬水平注：miR-377-3p.微小RNA-377-3p；FGFR1.成纤维细胞生长因子受体1；D-GalN. D-半乳糖胺；TNF-α.肿瘤坏死因子α；GAPDH.甘油醛-3-磷酸脱氢酶；a图为Western-blotting检测细胞中FGFR1表达水平；b图为Western-blotting检测细胞中自噬相关蛋白水平

表5 两组细胞FGFR1蛋白相对灰度值的比较（ ± s）

组别	样本数	FGFR1
NC组	3	1.00 ± 0.11
FGFR1组	3	2.62 ± 0.29
t值		8.975
P值		< 0.001

表5 两组细胞FGFR1蛋白相对灰度值的比较（ ± s）

组别	样本数	FGFR1
NC组	3	1.00 ± 0.11
FGFR1组	3	2.62 ± 0.29
t值		8.975
P值		< 0.001

表6 各组细胞自噬相关蛋白相对灰度值的比较（ ± s）

组别	样本数	Beclin-1	LC3Ⅱ/Ⅰ	p62
对照组	3	1.00 ± 0.07	1.00 ± 0.11	1.00 ± 0.10
模型组	3	0.31 ± 0.05^a	0.34 ± 0.07^a	2.66 ± 0.08^a
miR-377-3p mimic组	3	0.87 ± 0.09^b	0.95 ± 0.06^b	1.15 ± 0.08^b
miR-377-3p mimic + NC组	3	0.88 ± 0.10	1.05 ± 0.07	1.25 ± 0.09
miR-377-3p mimic + FGFR1组		0.28 ± 0.06^c	0.43 ± 0.06^c	3.18 ± 0.30^c
F值		63.840	61.590	127.800
P值		< 0.001	< 0.001	< 0.001

表6 各组细胞自噬相关蛋白相对灰度值的比较（ ± s）

组别	样本数	Beclin-1	LC3Ⅱ/Ⅰ	p62
对照组	3	1.00 ± 0.07	1.00 ± 0.11	1.00 ± 0.10
模型组	3	0.31 ± 0.05^a	0.34 ± 0.07^a	2.66 ± 0.08^a
miR-377-3p mimic组	3	0.87 ± 0.09^b	0.95 ± 0.06^b	1.15 ± 0.08^b
miR-377-3p mimic + NC组	3	0.88 ± 0.10	1.05 ± 0.07	1.25 ± 0.09
miR-377-3p mimic + FGFR1组		0.28 ± 0.06^c	0.43 ± 0.06^c	3.18 ± 0.30^c
F值		63.840	61.590	127.800
P值		< 0.001	< 0.001	< 0.001

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Mechanism of microRNA-377-3p regulating autophagy to ameliorate lipopolysaccharide / D-galactosamine-induced acute liver failure

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Mechanism of microRNA-377-3p regulating autophagy to ameliorate lipopolysaccharide / D-galactosamine-induced acute liver failure