长链非编码RNA在非酒精性脂肪性肝病发生发展中的调控作用

左志华; 曾楚怡; 姜瑶; 陶华林; 郭永灿

doi:10.3969/j.issn.1001-5256.2021.07.048

长链非编码RNA在非酒精性脂肪性肝病发生发展中的调控作用

DOI: 10.3969/j.issn.1001-5256.2021.07.048

左志华¹,
曾楚怡¹,
姜瑶¹,
陶华林^1, ,,
郭永灿^2, ,

1.
西南医科大学附属医院检验科, 四川泸州 646000
2.
西南医科大学附属中医医院检验科, 四川泸州 646000

基金项目:

泸州市人民政府-西南医科大学科技战略合作项目 (2018LZXNYD-ZK08)

利益冲突声明：所有作者均声明不存在利益冲突。

作者贡献声明：左志华负责课题设计, 资料分析, 起草论文; 曾楚怡、姜瑶参与资料分析, 修改论文; 陶华林、郭永灿负责拟定写作思路, 指导性支持并终审论文。

详细信息

通信作者:
陶华林, lzyxyjyx@163.com

郭永灿, guoyongcan_2004@163.com

中图分类号: R575.5
计量
- 文章访问数: 542
- HTML全文浏览量: 175
- PDF下载量: 50
- 被引次数: 0
出版历程
- 收稿日期: 2020-12-02
- 录用日期: 2020-12-18
- 出版日期: 2021-07-20

Regulatory role of long non-coding RNAs in the development and progression of nonalcoholic fatty liver disease

Zhihua ZUO¹,
Chuyi ZENG¹,
Yao JIANG¹,
Hualin TAO^{1
, ,},
Yongcan GUO^{2
, ,}

1.
Department of Clinical Laboratory, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China
2.
Department of Clinical Laboratory, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China

Research funding:

Luzhou Municipal People's Government & Southwest Medical University (2018LZXNYD-ZK08)

摘要

摘要: 非酒精性脂肪性肝病(NAFLD)是以肝细胞发生脂肪变性、脂质代谢紊乱以及异常沉积为特征的病理变化, 是最常见的肝脏疾病。长链非编码RNA(lncRNA)在NAFLD发生发展中的作用已成为当前的研究热点。总结了NAFLD中重要的lncRNA, 其主要参与调节脂质代谢、糖代谢、炎性变化等信号通路; 阐述了其促进NAFLD发生以及向肝炎、肝纤维化转变的作用机制。未来多基因组学和蛋白组学的深入研究将促进NAFLD精确的靶向治疗。
- 非酒精性脂肪性肝病 /
- RNA, 长链非编码 /
- 信号传导
Abstract: Nonalcoholic fatty liver disease (NAFLD) is characterized by fatty degeneration, lipid metabolism disorders, and abnormal deposition in hepatocytes, and it has become the most prevalent liver disease in the world. The role of long non-coding RNAs (lncRNAs) in the development and progression of NAFLD has become a hotspot at present. This article summarizes the key lncRNAs in NAFLD, which are mainly involved in the regulation of the signaling pathways including lipid metabolism, glucose metabolism, and inflammatory changes, and elaborates on the mechanism of action of lncRNAs in promoting the development of NAFLD or its transformation to hepatitis and liver fibrosis. It is pointed out that in-depth on polygenomics and proteomics will promote the precise targeted therapy of NAFLD.
- Non-Alcoholic Fatty Liver Disease /
- RNA, Long Untranslated /
- Signal Transduction

HTML全文

表 1 lncRNA在NAFLD中的调控通路与作用机制

lncRNA	全称	靶向通路	作用机制	文献
H19	-	miR-130a/PPARα	调节脂质代谢	[13]
		MLXIPL	促进肝脂肪变性	[14]
NEAT1	核富集转录体1	miR-146-5a/ROCK1/AMPK	促进脂质蓄积和脂肪变性	[15]
		miR-140/AMPK/SREBP-1		[16]
LncARSR	舒尼替尼耐药的肾细胞癌中活化的lncRNA	SREBP-1c、FASN	促进脂质合成和积累	[17]
FLRL	脂肪肝相关lncRNA	FABP5、LPL、FADS2	调节脂质代谢	[11]
		ARNTL/SIRT1	调节脂肪变性	[18]
SRA	类固醇受体RNA激活剂	ATGL/FOXO1	调节糖代谢和胰岛素抵抗	[19]
MEG3	lncRNA母系表达基因3	FOXO1	调节胰岛素抵抗	[20]
		miR-21/mTOR	调节脂质代谢	[21]
LncSHGL	肝脏糖异生和脂肪形成的lncRNA抑制剂	PI3K/Akt	调节糖代谢	[22]
		FOXO1	调节胰岛素抵抗	[7]
Lnc18q22.2	-	-	调节炎性反应	[23]
Blnc1	棕色富脂lncRNA	-	促进炎性因子释放和线粒体氧化应激	[24]
		LXR/SREBP1c	调节脂质代谢	[25]
GAS5	生长停滞特异性转录本5	miR-23a/PI3K/Akt/mTOR	促进肝纤维化	[26]
HULC	肝癌高度上调lncRNA	MAPK信号通路	促进肝纤维化和肝细胞凋亡	[27]
MALAT1	肺腺癌转移相关转录物1	SREBP-1c	调节脂质代谢	[28]
		TCF7L2	调节糖代谢	[29]
		CXCL5	促进肝细胞炎症和纤维化	[30]
注：PPARα, 过氧化物酶体增殖激活受体α; MLXIPL, MLX结合蛋白样基因; ROCK1, rho相关螺旋蛋白激酶1; AMPK, 蛋白激酶; FASN, 脂肪酸合成酶; FABP5, 脂肪酸结合蛋白5; LPL, 脂蛋白脂肪酶; FADS2, 脂肪酸去饱和酶2; ARNTL, 芳烃受体核转运蛋白样; SIRT1, NAD-依赖性的去乙酰化酶1; ATGL, 脂肪甘油三酯脂酶; FOXO1, 叉头框蛋白O1; mTOR, 哺乳动物雷帕霉素靶蛋白; PI3K, 磷酸肌醇3-激酶; Akt, 蛋白激酶B; LXR, 肝X受体; TCF7L2, 转录因子7类似物2; CXCL5, CXC趋化因子配体-5。

下载: 导出CSV

参考文献(41)

[1]	YOUNOSSI Z, TACKE F, ARRESE M, et al. Global perspectives on nonalcoholic fatty liver disease and nonalcoholic steatohepatitis[J]. Hepatology, 2019, 69(6): 2672-2682. DOI: 10.1002/hep.30251.
[2]	YOUNOSSI ZM, KOENIG AB, ABDELATIF D, et al. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes[J]. Hepatology, 2016, 64(1): 73-84. DOI: 10.1002/hep.28431.
[3]	ATANASOVSKA B, RENSEN SS, van der SIJDE MR, et al. A liver-specific long noncoding RNA with a role in cell viability is elevated in human nonalcoholic steatohepatitis[J]. Hepatology, 2017, 66(3): 794-808. DOI: 10.1002/hep.29034.
[4]	CHEN Q, XIONG C, JIA K, et al. Hepatic transcriptome analysis from HFD-fed mice defines a long noncoding RNA regulating cellular cholesterol levels[J]. J Lipid Res, 2019, 60(2): 341-352. DOI: 10.1194/jlr.M086215.
[5]	DANKO CG, HAH N, LUO X, et al. Signaling pathways differentially affect RNA polymerase Ⅱ initiation, pausing, and elongation rate in cells[J]. Mol Cell, 2013, 50(2): 212-222. DOI: 10.1016/j.molcel.2013.02.015.
[6]	GUO X, GAO L, WANG Y, et al. Advances in long noncoding RNAs: Identification, structure prediction and function annotation[J]. Brief Funct Genomics, 2016, 15(1): 38-46. DOI: 10.1093/bfgp/elv022.
[7]	HAN S, ZHANG T, KUSUMANCHI P, et al. Long non-coding RNAs in liver diseases: Focusing on nonalcoholic fatty liver disease, alcohol-related liver disease, and cholestatic liver disease[J]. Clin Mol Hepatol, 2020, 26(4): 705-714. DOI: 10.3350/cmh.2020.0166.
[8]	KOPP F, MENDELL JT. Functional classification and experimental dissection of long noncoding RNAs[J]. Cell, 2018, 172(3): 393-407. DOI: 10.1016/j.cell.2018.01.011.
[9]	MACDONALD WA, MANN M. Long noncoding RNA functionality in imprinted domain regulation[J]. PLoS Genet, 2020, 16(8): e1008930. DOI: 10.1371/journal.pgen.1008930.
[10]	SUN C, LIU X, YI Z, et al. Genome-wide analysis of long noncoding RNA expression profiles in patients with non-alcoholic fatty liver disease[J]. IUBMB Life, 2015, 67(11): 847-852. DOI: 10.1002/iub.1442.
[11]	CHEN Y, HUANG H, XU C, et al. Long non-coding RNA profiling in a non-alcoholic fatty liver disease rodent model: New insight into pathogenesis[J]. Int J Mol Sci, 2017, 18(1): 21. DOI: 10.3390/ijms18010021.
[12]	CHAO HW, CHAO SW, LIN H, et al. Homeostasis of glucose and lipid in non-alcoholic fatty liver disease[J]. Int J Mol Sci, 2019, 20(2): 298. DOI: 10.3390/ijms20020298.
[13]	LIU J, TANG T, WANG GD, et al. lncRNA-H19 promotes hepatic lipogenesis by directly regulating miR-130a/PPARγ axis in non-alcoholic fatty liver disease[J]. Biosci Rep, 2019, 39(7): BSR20181722. DOI: 10.1042/BSR20181722.
[14]	WANG H, CAO Y, SHU L, et al. Long non-coding RNA (lncRNA) H19 induces hepatic steatosis through activating MLXIPL and mTORC1 networks in hepatocytes[J]. J Cell Mol Med, 2020, 24(2): 1399-1412. DOI: 10.1111/jcmm.14818.
[15]	CHEN X, TAN XR, LI SJ, et al. lncRNA NEAT1 promotes hepatic lipid accumulation via regulating miR-146a-5p/ROCK1 in nonalcoholic fatty liver disease[J]. Life Sci, 2019, 235: 116829. DOI: 10.1016/j.lfs.2019.116829.
[16]	SUN Y, SONG Y, LIU C, et al. lncRNA NEAT1-MicroRNA-140 axis exacerbates nonalcoholic fatty liver through interrupting AMPK/SREBP-1 signaling[J]. Biochem Biophys Res Commun, 2019, 516(2): 584-590. DOI: 10.1016/j.bbrc.2019.06.104.
[17]	ZHANG M, CHI X, QU N, et al. Long noncoding RNA lncARSR promotes hepatic lipogenesis via Akt/SREBP-1c pathway and contributes to the pathogenesis of nonalcoholic steatohepatitis[J]. Biochem Biophys Res Commun, 2018, 499(1): 66-70. DOI: 10.1016/j.bbrc.2018.03.127.
[18]	CHEN Y, CHEN X, GAO J, et al. Long noncoding RNA FLRL2 alleviated nonalcoholic fatty liver disease through Arntl-Sirt1 pathway[J]. FASEB J, 2019, 33(10): 11411-11419. DOI: 10.1096/fj.201900643RRR.
[19]	CHEN G, YU D, NIAN X, et al. lncRNA SRA promotes hepatic steatosis through repressing the expression of adipose triglyceride lipase (ATGL)[J]. Sci Rep, 2016, 6: 35531. DOI: 10.1038/srep35531.
[20]	ZHU X, WU YB, ZHOU J, et al. Upregulation of lncRNA MEG3 promotes hepatic insulin resistance via increasing FoxO1 expression[J]. Biochem Biophys Res Commun, 2016, 469(2): 319-325. DOI: 10.1016/j.bbrc.2015.11.048.
[21]	HUANG P, HUANG FZ, LIU HZ, et al. lncRNA MEG3 functions as a ceRNA in regulating hepatic lipogenesis by competitively binding to miR-21 with LRP6[J]. Metabolism, 2019, 94: 1-8. DOI: 10.1016/j.metabol.2019.01.018.
[22]	WANG J, YANG W, CHEN Z, et al. Long noncoding RNA lncSHGL recruits hnRNPA1 to suppress hepatic gluconeogenesis and lipogenesis[J]. Diabetes, 2018, 67(4): 581-593. DOI: 10.2337/db17-0799.
[23]	ZHAO XY, LI S, DELPROPOSTO JL, et al. The long noncoding RNA Blnc1 orchestrates homeostatic adipose tissue remodeling to preserve metabolic health[J]. Mol Metab, 2018, 14: 60-70. DOI: 10.1016/j.molmet.2018.06.005.
[24]	TANG S, ZHU W, ZHENG F, et al. The long noncoding RNA Blnc1 protects against diet-induced obesity by promoting mitochondrial function in white fat[J]. Diabetes Metab Syndr Obes, 2020, 13: 1189-1201. DOI: 10.2147/DMSO.S248692.
[25]	ZHAO XY, XIONG X, LIU T, et al. Long noncoding RNA licensing of obesity-linked hepatic lipogenesis and NAFLD pathogenesis[J]. Nat Commun, 2018, 9(1): 2986. DOI: 10.1038/s41467-018-05383-2.
[26]	DONG Z, LI S, WANG X, et al. lncRNA GAS5 restrains CCl4-induced hepatic fibrosis by targeting miR-23a through the PTEN/PI3K/Akt signaling pathway[J]. Am J Physiol Gastrointest Liver Physiol, 2019, 316(4): G539-G550. DOI: 10.1152/ajpgi.00249.2018.
[27]	SHEN X, GUO H, XU J, et al. Inhibition of lncRNA HULC improves hepatic fibrosis and hepatocyte apoptosis by inhibiting the MAPK signaling pathway in rats with nonalcoholic fatty liver disease[J]. J Cell Physiol, 2019, 234(10): 18169-18179. DOI: 10.1002/jcp.28450.
[28]	YAN C, CHEN J, CHEN N. Long noncoding RNA MALAT1 promotes hepatic steatosis and insulin resistance by increasing nuclear SREBP-1c protein stability[J]. Sci Rep, 2016, 6: 22640. DOI: 10.1038/srep22640.
[29]	MALAKAR P, STEIN I, SARAGOVI A, et al. Long noncoding RNA MALAT1 regulates cancer glucose metabolism by enhancing mTOR-mediated translation of TCF7L2[J]. Cancer Res, 2019, 79(10): 2480-2493. DOI: 10.1158/0008-5472.CAN-18-1432.
[30]	LETI F, LEGENDRE C, STILL CD, et al. Altered expression of MALAT1 lncRNA in nonalcoholic steatohepatitis fibrosis regulates CXCL5 in hepatic stellate cells[J]. Transl Res, 2017, 190: 25-39.e21. DOI: 10.1016/j.trsl.2017.09.001.
[31]	BU FT, WANG A, ZHU Y, et al. lncRNA NEAT1: Shedding light on mechanisms and opportunities in liver diseases[J]. Liver Int, 2020, 40(11): 2612-2626. DOI: 10.1111/liv.14629.
[32]	WANG X. Down-regulation of lncRNA-NEAT1 alleviated the non-alcoholic fatty liver disease via mTOR/S6K1 signaling pathway[J]. J Cell Biochem, 2018, 119(2): 1567-1574. DOI: 10.1002/jcb.26317.
[33]	CHI Y, GONG Z, XIN H, et al. Long noncoding RNA lncARSR promotes nonalcoholic fatty liver disease and hepatocellular carcinoma by promoting YAP1 and activating the IRS2/AKT pathway[J]. J Transl Med, 2020, 18(1): 126. DOI: 10.1186/s12967-020-02225-y.
[34]	CHOONIEDASS-KOTHARI S, VINCETT D, YAN Y, et al. The protein encoded by the functional steroid receptor RNA activator is a new modulator of ER alpha transcriptional activity[J]. FEBS Lett, 2010, 584(6): 1174-1180. DOI: 10.1016/j.febslet.2010.02.024.
[35]	CHAKRABARTI P, KANDROR KV. FoxO1 controls insulin-dependent adipose triglyceride lipase (ATGL) expression and lipolysis in adipocytes[J]. J Biol Chem, 2009, 284(20): 13296-13300. DOI: 10.1074/jbc.C800241200.
[36]	CHUNHAROJRITH P, NAKAYAMA Y, JIANG X, et al. Tumor suppression by MEG3 lncRNA in a human pituitary tumor derived cell line[J]. Mol Cell Endocrinol, 2015, 416: 27-35. DOI: 10.1016/j.mce.2015.08.018.
[37]	WANG X, WANG J. High-content hydrogen water-induced downregulation of miR-136 alleviates non-alcoholic fatty liver disease by regulating Nrf2 via targeting MEG3[J]. Biol Chem, 2018, 399(4): 397-406. DOI: 10.1515/hsz-2017-0303.
[38]	WANG Y, JING W, MA W, et al. Down-regulation of long non-coding RNA GAS5-AS1 and its prognostic and diagnostic significance in hepatocellular carcinoma[J]. Cancer Biomark, 2018, 22(2): 227-236. DOI: 10.3233/CBM-170781.
[39]	XIONG H, LI B, HE J, et al. lncRNA HULC promotes the growth of hepatocellular carcinoma cells via stabilizing COX-2 protein[J]. Biochem Biophys Res Commun, 2017, 490(3): 693-699. DOI: 10.1016/j.bbrc.2017.06.103.
[40]	PENG H, WANG J, LI J, et al. A circulating non-coding RNA panel as an early detection predictor of non-small cell lung cancer[J]. Life Sci, 2016, 151: 235-242. DOI: 10.1016/j.lfs.2016.03.002.
[41]	SOOKOIAN S, FLICHMAN D, GARAYCOECHEA ME, et al. Metastasis-associated lung adenocarcinoma transcript 1 as a common molecular driver in the pathogenesis of nonalcoholic steatohepatitis and chronic immune-mediated liver damage[J]. Hepatol Commun, 2018, 2(6): 654-665. DOI: 10.1002/hep4.1184.