Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China
alfredhc@sjtu.edu.cn
Show less
History+
Received
Accepted
Published Online
2016-04-23
2016-07-05
2016-08-19
PDF
(204KB)
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a major cause of liver cirrhosis and hepatocellular carcinoma and is a considerable threat to public health. miRNAs are important post-transcriptional regulators of gene expression, and the dysregulation of miRNAs is involved in various biological processes in the liver, including lipid homeostasis, inflammation, apoptosis, and cell proliferation. Recently, a number of studies have described the association between miRNAs and NAFLD progression and have shown that circulating miRNAs reflect histological changes in the liver. Therefore, circulating miRNAs have potential use for the evaluation of NAFLD severity. In this review, we discuss the involvement of miRNAs in NAFLD pathogenesis and the key role of miRNAs in the screening, diagnosis, and staging of NAFLD.
YounossiZM, KoenigAB, AbdelatifD, FazelY, HenryL, WymerM. Global epidemiology of non-alcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence and outcomes. Hepatology2015; 64(1): 73–84
[2]
VernonG, BaranovaA, YounossiZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther2011; 34(3): 274–285
[3]
AttarBM, Van ThielDH. Current concepts and management approaches in nonalcoholic fatty liver disease. Sci World J2013; 2013: 481893
[4]
Yki-JärvinenH. Non-alcoholic fatty liver disease as a cause and a consequence of metabolic syndrome. Lancet Diabetes Endocrinol2014; 2(11): 901–910
[5]
ThanNN, NewsomePN. A concise review of non-alcoholic fatty liver disease. Atherosclerosis2015; 239(1): 192–202
[6]
Ul HussainM. Micro-RNAs (miRNAs): genomic organisation, biogenesis and mode of action. Cell Tissue Res2012; 349(2): 405–413
[7]
WangXW, HeegaardNH, OrumH. MicroRNAs in liver disease. Gastroenterology2012; 142(7): 1431–1443
[8]
PirolaCJ, Fernández GianottiT, CastañoGO, MallardiP, San MartinoJ, Mora Gonzalez Lopez LedesmaM, FlichmanD, MirshahiF, SanyalAJ, SookoianS. Circulating microRNA signature in non-alcoholic fatty liver disease: from serum non-coding RNAs to liver histology and disease pathogenesis. Gut2015; 64(5): 800–812
[9]
LiS, ChenX, ZhangH, LiangX, XiangY, YuC, ZenK, LiY, ZhangCY. Differential expression of microRNAs in mouse liver under aberrant energy metabolic status. J Lipid Res2009; 50(9): 1756–1765
SzaboG, CsakT. Role of microRNAs in NAFLD/NASH. Dig Dis Sci2016; 61(5): 1314–1324
[12]
TessitoreA, CicciarelliG, Del VecchioF, GaggianoA, VerzellaD, FischiettiM, MastroiacoV, VetuschiA, SferraR, BarnabeiR, CapeceD, ZazzeroniF, AlesseE. MicroRNA expression analysis in high fat diet-induced NAFLD-NASH-HCC progression: study on C57BL/6J mice. BMC Cancer2016; 16(1): 3
[13]
TsaiWC, HsuSD, HsuCS, LaiTC, ChenSJ, ShenR, HuangY, ChenHC, LeeCH, TsaiTF, HsuMT, WuJC, HuangHD, ShiaoMS, HsiaoM, TsouAP. MicroRNA-122 plays a critical role in liver homeostasis and hepatocarcinogenesis. J Clin Invest2012; 122(8): 2884–2897
[14]
MooreKJ, RaynerKJ, SuárezY, Fernández-HernandoC. The role of microRNAs in cholesterol efflux and hepatic lipid metabolism. Annu Rev Nutr2011; 31(1): 49–63
[15]
EsauC, DavisS, MurraySF, YuXX, PandeySK, PearM, WattsL, BootenSL, GrahamM, McKayR, SubramaniamA, ProppS, LolloBA, FreierS, BennettCF, BhanotS, MoniaBP. miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab2006; 3(2): 87–98
[16]
CsakT, BalaS, LippaiD, SatishchandranA, CatalanoD, KodysK, SzaboG. microRNA-122 regulates hypoxia-inducible factor-1 and vimentin in hepatocytes and correlates with fibrosis in diet-induced steatohepatitis. Liver Int2015; 35(2): 532–541
[17]
HortonJD, GoldsteinJL, BrownMS. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest2002; 109(9): 1125–1131
[18]
JeonTI, OsborneTF. SREBPs: metabolic integrators in physiology and metabolism. Trends Endocrinol Metab2012; 23(2): 65–72
[19]
Najafi-ShoushtariSH, KristoF, LiY, ShiodaT, CohenDE, GersztenRE, NäärAM. MicroRNA-33 and the SREBP host genes cooperate to control cholesterol homeostasis. Science2010; 328(5985): 1566–1569
[20]
DávalosA, GoedekeL, SmibertP, RamírezCM, WarrierNP, AndreoU, Cirera-SalinasD, RaynerK, SureshU, Pastor-ParejaJC, EspluguesE, FisherEA, PenalvaLO, MooreKJ, SuárezY, LaiEC, Fernández-HernandoC. miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling. Proc Natl Acad Sci USA2011; 108(22): 9232–9237
[21]
RaynerKJ, EsauCC, HussainFN, McDanielAL, MarshallSM, van GilsJM, RayTD, SheedyFJ, GoedekeL, LiuX, KhatsenkoOG, KaimalV, LeesCJ, Fernandez-HernandoC, FisherEA, TemelRE, MooreKJ. Inhibition of miR-33a/b in non-human primates raises plasma HDL and lowers VLDL triglycerides. Nature2011; 478(7369): 404–407
DingJ, LiM, WanX, JinX, ChenS, YuC, LiY. Effect of miR-34a in regulating steatosis by targeting PPARa expression in nonalcoholic fatty liver disease. Sci Rep2015; 5: 13729
[26]
DerdakZ, VillegasKA, HarbR, WuAM, SousaA, WandsJR. Inhibition of p53 attenuates steatosis and liver injury in a mouse model of non-alcoholic fatty liver disease. J Hepatol2013; 58(4): 785–791
[27]
XuY, ZalzalaM, XuJ, LiY, YinL, ZhangY. A metabolic stress-inducible miR-34a-HNF4a pathway regulates lipid and lipoprotein metabolism. Nat Commun2015; 6: 7466
[28]
HayhurstGP, LeeYH, LambertG, WardJM, GonzalezFJ. Hepatocyte nuclear factor 4α (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis. Mol Cell Biol2001; 21(4): 1393–1403
[29]
YinL, MaH, GeX, EdwardsPA, ZhangY. Hepatic hepatocyte nuclear factor 4a is essential for maintaining triglyceride and cholesterol homeostasis. Arterioscler Thromb Vasc Biol2011; 31(2): 328–336
[30]
ShanW, GaoL, ZengW, HuY, WangG, LiM, ZhouJ, MaX, TianX, YaoJ.Activation of the SIRT1/p66shc antiapoptosis pathway via carnosic acid-induced inhibition of miR-34a protects rats against nonalcoholic fatty liver disease. Cell Death Dis2015; 6: e1833
[31]
SunC, HuangF, LiuX, XiaoX, YangM, HuG, LiuH, LiaoL. miR-21 regulates triglyceride and cholesterol metabolism in non-alcoholic fatty liver disease by targeting HMGCR. Int J Mol Med2015; 35(3): 847–853
[32]
AhnJ, LeeH, JungCH, HaT. Lycopene inhibits hepatic steatosis via microRNA-21-induced downregulation of fatty acid-binding protein 7 in mice fed a high-fat diet. Mol Nutr Food Res2012; 56(11): 1665–1674
[33]
LoyerX, ParadisV, HéniqueC, VionAC, ColnotN, GuerinCL, DevueC, OnS, ScetbunJ, RomainM, PaulJL, RothenbergME, MarcellinP, DurandF, BedossaP, Prip-BuusC, BaugéE, StaelsB, BoulangerCM, TedguiA, RautouPE. Liver microRNA-21 is overexpressed in non-alcoholic steatohepatitis and contributes to the disease in experimental models by inhibiting PPARa expression. Gut2015 Sep 3. [Epub ahead of print]
[34]
ReddyJK, RaoMS. Lipid metabolism and liver inflammation. II. Fatty liver disease and fatty acid oxidation. Am J Physiol Gastrointest Liver Physiol2006; 290(5): G852–G858
[35]
YangL, RohYS, SongJ, ZhangB, LiuC, LoombaR, SekiE. Transforming growth factor beta signaling in hepatocytes participates in steatohepatitis through regulation of cell death and lipid metabolism in mice. Hepatology2014; 59(2): 483–495
[36]
DattaroyD, PourhoseiniS, DasS, AlhassonF, SethRK, NagarkattiM, MichelottiGA, DiehlAM, ChatterjeeS. MicroRNA 21 inhibition of SMAD7 enhances fibrogenesis via leptin-mediated NADPH oxidase in experimental and human nonalcoholic steatohepatitis. Am J Physiol Gastrointest Liver Physiol2015; 308(4): G298–G312
[37]
WuH, NgR, ChenX, SteerCJ, SongG. MicroRNA-21 is a potential link between non-alcoholic fatty liver disease and hepatocellular carcinoma via modulation of the HBP1-p53-Srebp1c pathway. Gut2015 Aug 17. [Epub ahead of print]
[38]
VinciguerraM, SgroiA, Veyrat-DurebexC, Rubbia-BrandtL, BuhlerLH, FotiM. Unsaturated fatty acids inhibit the expression of tumor suppressor phosphatase and tensin homolog (PTEN) via microRNA-21 up-regulation in hepatocytes. Hepatology2009; 49(4): 1176–1184
[39]
HeY, HuangC, LinX, LiJ. MicroRNA-29 family, a crucial therapeutic target for fibrosis diseases. Biochimie2013; 95(7): 1355–1359
[40]
PogribnyIP, Starlard-DavenportA, TryndyakVP, HanT, RossSA, RusynI, BelandFA. Difference in expression of hepatic microRNAs miR-29c, miR-34a, miR-155, and miR-200b is associated with strain-specific susceptibility to dietary nonalcoholic steatohepatitis in mice. Lab Invest2010; 90(10): 1437–1446
[41]
MattisAN, SongG, HitchnerK, KimRY, LeeAY, SharmaAD, MalatoY, McManusMT, EsauCC, KollerE, KoliwadS, LimLP, MaherJJ, RaffaiRL, WillenbringH. A screen in mice uncovers repression of lipoprotein lipase by microRNA-29a as a mechanism for lipid distribution away from the liver. Hepatology2015; 61(1): 141–152
[42]
AhnJ, LeeH, ChungCH, HaT. High fat diet induced downregulation of microRNA-467b increased lipoprotein lipase in hepatic steatosis. Biochem Biophys Res Commun2011; 414(4): 664–669
[43]
KurtzCL, FanninEE, TothCL, PearsonDS, VickersKC, SethupathyP. Inhibition of miR-29 has a significant lipid-lowering benefit through suppression of lipogenic programs in liver. Sci Rep2015; 5: 12911
[44]
XiaoJ, BeiY, LiuJ, Dimitrova-ShumkovskaJ, KuangD, ZhouQ, LiJ, YangY, XiangY, WangF, YangC, YangW. miR-212 downregulation contributes to the protective effect of exercise against non-alcoholic fatty liver via targeting FGF-21. J Cell Mol Med2016; 20(2): 204–216
[45]
ZhangZC, LiuY, XiaoLL, LiSF, JiangJH, ZhaoY, QianSW, TangQQ, LiX. Upregulation of miR-125b by estrogen protects against non-alcoholic fatty liver in female mice. J Hepatol2015; 63(6): 1466–1475
[46]
NgR, WuH, XiaoH, ChenX, WillenbringH, SteerCJ, SongG. Inhibition of microRNA-24 expression in liver prevents hepatic lipid accumulation and hyperlipidemia. Hepatology2014; 60(2): 554–564
[47]
WangB, MajumderS, NuovoG, KutayH, VoliniaS, PatelT, SchmittgenTD, CroceC, GhoshalK, JacobST. Role of microRNA-155 at early stages of hepatocarcinogenesis induced by choline-deficient and amino acid-defined diet in C57BL/6 mice. Hepatology2009; 50(4): 1152–1161
[48]
LeeSS, ParkSH. Radiologic evaluation of nonalcoholic fatty liver disease. World J Gastroenterol2014; 20(23): 7392–7402
[49]
PoveroD, EguchiA, LiH, JohnsonCD, PapouchadoBG, WreeA, MesserK, FeldsteinAE. Circulating extracellular vesicles with specific proteome and liver microRNAs are potential biomarkers for liver injury in experimental fatty liver disease. PLoS ONE2014; 9(12): e113651
[50]
YamadaH, SuzukiK, IchinoN, AndoY, SawadaA, OsakabeK, SugimotoK, OhashiK, TeradairaR, InoueT, HamajimaN, HashimotoS. Associations between circulating microRNAs (miR-21, miR-34a, miR-122 and miR-451) and non-alcoholic fatty liver. Clin Chim Acta2013; 424: 99–103
[51]
YamadaH, OhashiK, SuzukiK, MunetsunaE, AndoY, YamazakiM, IshikawaH, IchinoN, TeradairaR, HashimotoS. Longitudinal study of circulating miR-122 in a rat model of non-alcoholic fatty liver disease. Clin Chim Acta2015; 446: 267–271
[52]
ClarkeJD, SharapovaT, LakeAD, BlommeE, MaherJ, CherringtonNJ. Circulating microRNA 122 in the methionine and choline-deficient mouse model of non-alcoholic steatohepatitis. J Appl Toxicol2014; 34(6): 726–732
[53]
MiyaakiH, IchikawaT, KamoY, TauraN, HondaT, ShibataH, MilazzoM, FornariF, GramantieriL, BolondiL, NakaoK. Significance of serum and hepatic microRNA-122 levels in patients with non-alcoholic fatty liver disease. Liver Int2014; 34(7): e302–e307
[54]
CermelliS, RuggieriA, MarreroJA, IoannouGN, BerettaL. Circulating microRNAs in patients with chronic hepatitis C and non-alcoholic fatty liver disease. PLoS ONE2011; 6(8): e23937
[55]
CelikbilekM, BaskolM, TaheriS, DenizK, DoganS, ZararsizG, GursoyS, GuvenK, OzbakırO, DundarM, YucesoyM. Circulating microRNAs in patients with non-alcoholic fatty liver disease. World J Hepatol2014; 6(8): 613–620
[56]
TanY, GeG, PanT, WenD, GanJ. A pilot study of serum microRNAs panel as potential biomarkers for diagnosis of nonalcoholic fatty liver disease. PLoS ONE2014; 9(8): e105192
RIGHTS & PERMISSIONS
Higher Education Press and Springer-Verlag Berlin Heidelberg