Frontiers of Medicine

, Volume 10, Issue 4, pp 389–396 | Cite as

miRNAs in non-alcoholic fatty liver disease

  • Zhen He
  • Cheng Hu
  • Weiping Jia


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.


nonalcoholic fatty liver disease nonalcoholic steatohepatitis hepatocellular carcinoma miRNA 


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  1. 1.
    Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of non-alcoholic fatty liver disease-metaanalytic assessment of prevalence, incidence and outcomes. Hepatology 2015; 64(1): 73–84CrossRefGoogle Scholar
  2. 2.
    Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther 2011; 34(3): 274–285CrossRefPubMedGoogle Scholar
  3. 3.
    Attar BM, Van Thiel DH. Current concepts and management approaches in nonalcoholic fatty liver disease. Sci World J 2013; 2013: 481893CrossRefGoogle Scholar
  4. 4.
    Yki-Järvinen H. Non-alcoholic fatty liver disease as a cause and a consequence of metabolic syndrome. Lancet Diabetes Endocrinol 2014; 2(11): 901–910CrossRefPubMedGoogle Scholar
  5. 5.
    Than NN, Newsome PN. A concise review of non-alcoholic fatty liver disease. Atherosclerosis 2015; 239(1): 192–202CrossRefPubMedGoogle Scholar
  6. 6.
    Ul Hussain M. Micro-RNAs (miRNAs): genomic organisation, biogenesis and mode of action. Cell Tissue Res 2012; 349(2): 405–413CrossRefPubMedGoogle Scholar
  7. 7.
    Wang XW, Heegaard NH, Orum H. MicroRNAs in liver disease. Gastroenterology 2012; 142(7): 1431–1443CrossRefPubMedGoogle Scholar
  8. 8.
    Pirola CJ, Fernández Gianotti T, Castaño GO, Mallardi P, San Martino J, Mora Gonzalez Lopez Ledesma M, Flichman D, Mirshahi F, Sanyal AJ, Sookoian S. Circulating microRNA signature in non-alcoholic fatty liver disease: from serum non-coding RNAs to liver histology and disease pathogenesis. Gut 2015; 64(5): 800–812CrossRefPubMedGoogle Scholar
  9. 9.
    Li S, Chen X, Zhang H, Liang X, Xiang Y, Yu C, Zen K, Li Y, Zhang CY. Differential expression of microRNAs in mouse liver under aberrant energy metabolic status. J Lipid Res 2009; 50(9): 1756–1765CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Cheung O, Puri P, Eicken C, Contos MJ, Mirshahi F, Maher JW, Kellum JM, Min H, Luketic VA, Sanyal AJ. Nonalcoholic steatohepatitis is associated with altered hepatic microRNA expression. Hepatology 2008; 48(6): 1810–1820CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Szabo G, Csak T. Role of microRNAs in NAFLD/NASH. Dig Dis Sci 2016; 61(5): 1314–1324CrossRefPubMedGoogle Scholar
  12. 12.
    Tessitore A, Cicciarelli G, Del Vecchio F, Gaggiano A, Verzella D, Fischietti M, Mastroiaco V, Vetuschi A, Sferra R, Barnabei R, Capece D, Zazzeroni F, Alesse E. MicroRNA expression analysis in high fat diet-induced NAFLD-NASH-HCC progression: study on C57BL/6J mice. BMC Cancer 2016; 16(1): 3CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Tsai WC, Hsu SD, Hsu CS, Lai TC, Chen SJ, Shen R, Huang Y, Chen HC, Lee CH, Tsai TF, Hsu MT, Wu JC, Huang HD, Shiao MS, Hsiao M, Tsou AP. MicroRNA-122 plays a critical role in liver homeostasis and hepatocarcinogenesis. J Clin Invest 2012; 122(8): 2884–2897CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Moore KJ, Rayner KJ, Suárez Y, Fernández-Hernando C. The role of microRNAs in cholesterol efflux and hepatic lipid metabolism. Annu Rev Nutr 2011; 31(1): 49–63CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Esau C, Davis S, Murray SF, Yu XX, Pandey SK, Pear M, Watts L, Booten SL, Graham M, Mc Kay R, Subramaniam A, Propp S, Lollo BA, Freier S, Bennett CF, Bhanot S, Monia BP. miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab 2006; 3(2): 87–98CrossRefPubMedGoogle Scholar
  16. 16.
    Csak T, Bala S, Lippai D, Satishchandran A, Catalano D, Kodys K, Szabo G. microRNA-122 regulates hypoxia-inducible factor-1 and vimentin in hepatocytes and correlates with fibrosis in diet-induced steatohepatitis. Liver Int 2015; 35(2): 532–541CrossRefPubMedGoogle Scholar
  17. 17.
    Horton JD, Goldstein JL, Brown MS. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest 2002; 109(9): 1125–1131CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Jeon TI, Osborne TF. SREBPs: metabolic integrators in physiology and metabolism. Trends Endocrinol Metab 2012; 23(2): 65–72CrossRefPubMedGoogle Scholar
  19. 19.
    Najafi-Shoushtari SH, Kristo F, Li Y, Shioda T, Cohen DE, Gerszten RE, Näär AM. MicroRNA-33 and the SREBP host genes cooperate to control cholesterol homeostasis. Science 2010; 328 (5985): 1566–1569CrossRefPubMedGoogle Scholar
  20. 20.
    Dávalos A, Goedeke L, Smibert P, Ramírez CM, Warrier NP, Andreo U, Cirera-Salinas D, Rayner K, Suresh U, Pastor-Pareja JC, Esplugues E, Fisher EA, Penalva LO, Moore KJ, Suárez Y, Lai EC, Fernández-Hernando C. miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling. Proc Natl Acad Sci USA 2011; 108(22): 9232–9237CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Rayner KJ, Esau CC, Hussain FN, McDaniel AL, Marshall SM, van Gils JM, Ray TD, Sheedy FJ, Goedeke L, Liu X, Khatsenko OG, Kaimal V, Lees CJ, Fernandez-Hernando C, Fisher EA, Temel RE, Moore KJ. Inhibition of miR-33a/b in non-human primates raises plasma HDL and lowers VLDL triglycerides. Nature 2011; 478 (7369): 404–407CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Goedeke L, Salerno A, Ramírez CM, Guo L, Allen RM, Yin X, Langley SR, Esau C, Wanschel A, Fisher EA, Suárez Y, Baldán A, Mayr M, Fernández-Hernando C. Long-term therapeutic silencing of miR-33 increases circulating triglyceride levels and hepatic lipid accumulation in mice. EMBO Mol Med 2014; 6(9): 1133–1141CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Vega-Badillo J, Gutiérrez-Vidal R, Hernández-Pérez HA, Villamil-Ramírez H, León-Mimila P, Sánchez-Muñoz F, Morán-Ramos S, Larrieta-Carrasco E, Fernández-Silva I, Méndez-Sánchez N, Tovar AR, Campos-Pérez F, Villarreal-Molina T, Hernández-Pando R, Aguilar-Salinas CA, Canizales-Quinteros S. Hepatic miR-33a/miR-144 and their target gene ABCA1 are associated with steatohepatitis in morbidly obese subjects. Liver Int 2016 Mar 4. [Epub ahead of print] doi: 10.1111/liv.13109Google Scholar
  24. 24.
    Cirera-Salinas D, Pauta M, Allen RM, Salerno AG, Ramírez CM, Chamorro-Jorganes A, Wanschel AC, Lasuncion MA, Morales-Ruiz M, Suarez Y, Baldan Á, Esplugues E, Fernández-Hernando C. mir-33 regulates cell proliferation and cell cycle progression. Cell Cycle 2012; 11(5): 922–933CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Ding J, Li M, Wan X, Jin X, Chen S, Yu C, Li Y. Effect of miR-34a in regulating steatosis by targeting PPARa expression in nonalcoholic fatty liver disease. Sci Rep 2015; 5: 13729CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Derdak Z, Villegas KA, Harb R, Wu AM, Sousa A, Wands JR. Inhibition of p53 attenuates steatosis and liver injury in a mouse model of non-alcoholic fatty liver disease. J Hepatol 2013; 58(4): 785–791CrossRefPubMedGoogle Scholar
  27. 27.
    Xu Y, Zalzala M, Xu J, Li Y, Yin L, Zhang Y. A metabolic stressinducible miR-34a-HNF4a pathway regulates lipid and lipoprotein metabolism. Nat Commun 2015; 6: 7466CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Hayhurst GP, Lee YH, Lambert G, Ward JM, Gonzalez FJ. Hepatocyte nuclear factor 4a (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis. Mol Cell Biol 2001; 21(4): 1393–1403CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Yin L, Ma H, Ge X, Edwards PA, Zhang Y. Hepatic hepatocyte nuclear factor 4a is essential for maintaining triglyceride and cholesterol homeostasis. Arterioscler Thromb Vasc Biol 2011; 31 (2): 328–336CrossRefPubMedGoogle Scholar
  30. 30.
    Shan W, Gao L, Zeng W, Hu Y, Wang G, Li M, Zhou J, Ma X, Tian X, Yao J.Activation of the SIRT1/p66shc antiapoptosis pathway via carnosic acid-induced inhibition of miR-34a protects rats against nonalcoholic fatty liver disease. Cell Death Dis 2015; 6: e1833Google Scholar
  31. 31.
    Sun C, Huang F, Liu X, Xiao X, Yang M, Hu G, Liu H, Liao L. miR-21 regulates triglyceride and cholesterol metabolism in nonalcoholic fatty liver disease by targeting HMGCR. Int J Mol Med 2015; 35(3): 847–853CrossRefPubMedGoogle Scholar
  32. 32.
    Ahn J, Lee H, Jung CH, Ha T. 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 Res 2012; 56 (11): 1665–1674CrossRefPubMedGoogle Scholar
  33. 33.
    Loyer X, Paradis V, Hénique C, Vion AC, Colnot N, Guerin CL, Devue C, On S, Scetbun J, Romain M, Paul JL, Rothenberg ME, Marcellin P, Durand F, Bedossa P, Prip-Buus C, Baugé E, Staels B, Boulanger CM, Tedgui A, Rautou PE. Liver microRNA-21 is overexpressed in non-alcoholic steatohepatitis and contributes to the disease in experimental models by inhibiting PPARa expression. Gut 2015 Sep 3. [Epub ahead of print] doi: 10.1136/gutjnl-2014-308883Google Scholar
  34. 34.
    Reddy JK, Rao MS. Lipid metabolism and liver inflammation. II. Fatty liver disease and fatty acid oxidation. Am J Physiol Gastrointest Liver Physiol 2006; 290(5): G852–G858CrossRefPubMedGoogle Scholar
  35. 35.
    Yang L, Roh YS, Song J, Zhang B, Liu C, Loomba R, Seki E. Transforming growth factor beta signaling in hepatocytes participates in steatohepatitis through regulation of cell death and lipid metabolism in mice. Hepatology 2014; 59(2): 483–495CrossRefPubMedGoogle Scholar
  36. 36.
    Dattaroy D, Pourhoseini S, Das S, Alhasson F, Seth RK, Nagarkatti M, Michelotti GA, Diehl AM, Chatterjee S. MicroRNA 21 inhibition of SMAD7 enhances fibrogenesis via leptin-mediated NADPH oxidase in experimental and human nonalcoholic steatohepatitis. Am J Physiol Gastrointest Liver Physiol 2015; 308(4): G298–G312CrossRefPubMedGoogle Scholar
  37. 37.
    Wu H, Ng R, Chen X, Steer CJ, Song G. MicroRNA-21 is a potential link between non-alcoholic fatty liver disease and hepatocellular carcinoma via modulation of the HBP1-p53-Srebp1c pathway. Gut 2015 Aug 17. [Epub ahead of print] doi: 10.1136/gutjnl-2014-308430Google Scholar
  38. 38.
    Vinciguerra M, Sgroi A, Veyrat-Durebex C, Rubbia-Brandt L, Buhler LH, Foti M. Unsaturated fatty acids inhibit the expression of tumor suppressor phosphatase and tensin homolog (PTEN) via microRNA-21 up-regulation in hepatocytes. Hepatology 2009; 49 (4): 1176–1184CrossRefPubMedGoogle Scholar
  39. 39.
    He Y, Huang C, Lin X, Li J. MicroRNA-29 family, a crucial therapeutic target for fibrosis diseases. Biochimie 2013; 95(7): 1355–1359CrossRefPubMedGoogle Scholar
  40. 40.
    Pogribny IP, Starlard-Davenport A, Tryndyak VP, Han T, Ross SA, Rusyn I, Beland FA. 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 Invest 2010; 90(10): 1437–1446CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Mattis AN, Song G, Hitchner K, Kim RY, Lee AY, Sharma AD, Malato Y, McManus MT, Esau CC, Koller E, Koliwad S, Lim LP, Maher JJ, Raffai RL, Willenbring H. A screen in mice uncovers repression of lipoprotein lipase by microRNA-29a as a mechanism for lipid distribution away from the liver. Hepatology 2015; 61(1): 141–152CrossRefPubMedGoogle Scholar
  42. 42.
    Ahn J, Lee H, Chung CH, Ha T. High fat diet induced downregulation of microRNA-467b increased lipoprotein lipase in hepatic steatosis. Biochem Biophys Res Commun 2011; 414(4): 664–669CrossRefPubMedGoogle Scholar
  43. 43.
    Kurtz CL, Fannin EE, Toth CL, Pearson DS, Vickers KC, Sethupathy P. Inhibition of miR-29 has a significant lipid-lowering benefit through suppression of lipogenic programs in liver. Sci Rep 2015; 5: 12911CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Xiao J, Bei Y, Liu J, Dimitrova-Shumkovska J, Kuang D, Zhou Q, Li J, Yang Y, Xiang Y, Wang F, Yang C, Yang W. miR-212 downregulation contributes to the protective effect of exercise against non-alcoholic fatty liver via targeting FGF-21. J Cell Mol Med 2016; 20(2): 204–216CrossRefPubMedGoogle Scholar
  45. 45.
    Zhang ZC, Liu Y, Xiao LL, Li SF, Jiang JH, Zhao Y, Qian SW, Tang QQ, Li X. Upregulation of miR-125b by estrogen protects against non-alcoholic fatty liver in female mice. J Hepatol 2015; 63 (6): 1466–1475CrossRefPubMedGoogle Scholar
  46. 46.
    Ng R, Wu H, Xiao H, Chen X, Willenbring H, Steer CJ, Song G. Inhibition of microRNA-24 expression in liver prevents hepatic lipid accumulation and hyperlipidemia. Hepatology 2014; 60(2): 554–564CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Wang B, Majumder S, Nuovo G, Kutay H, Volinia S, Patel T, Schmittgen TD, Croce C, Ghoshal K, Jacob ST. Role of microRNA-155 at early stages of hepatocarcinogenesis induced by cholinedeficient and amino acid-defined diet in C57BL/6 mice. Hepatology 2009; 50(4): 1152–1161CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Lee SS, Park SH. Radiologic evaluation of nonalcoholic fatty liver disease. World J Gastroenterol 2014; 20(23): 7392–7402CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Povero D, Eguchi A, Li H, Johnson CD, Papouchado BG, Wree A, Messer K, Feldstein AE. Circulating extracellular vesicles with specific proteome and liver microRNAs are potential biomarkers for liver injury in experimental fatty liver disease. PLoS ONE 2014; 9 (12): e113651CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Yamada H, Suzuki K, Ichino N, Ando Y, Sawada A, Osakabe K, Sugimoto K, Ohashi K, Teradaira R, Inoue T, Hamajima N, Hashimoto S. Associations between circulating microRNAs (miR- 21, miR-34a, miR-122 and miR-451) and non-alcoholic fatty liver. Clin Chim Acta 2013; 424: 99–103CrossRefPubMedGoogle Scholar
  51. 51.
    Yamada H, Ohashi K, Suzuki K, Munetsuna E, Ando Y, Yamazaki M, Ishikawa H, Ichino N, Teradaira R, Hashimoto S. Longitudinal study of circulating miR-122 in a rat model of non-alcoholic fatty liver disease. Clin Chim Acta 2015; 446: 267–271CrossRefPubMedGoogle Scholar
  52. 52.
    Clarke JD, Sharapova T, Lake AD, Blomme E, Maher J, Cherrington NJ. Circulating microRNA 122 in the methionine and choline-deficient mouse model of non-alcoholic steatohepatitis. J Appl Toxicol 2014; 34(6): 726–732CrossRefPubMedGoogle Scholar
  53. 53.
    Miyaaki H, Ichikawa T, Kamo Y, Taura N, Honda T, Shibata H, Milazzo M, Fornari F, Gramantieri L, Bolondi L, Nakao K. Significance of serum and hepatic microRNA-122 levels in patients with non-alcoholic fatty liver disease. Liver Int 2014; 34(7): e302–e307CrossRefPubMedGoogle Scholar
  54. 54.
    Cermelli S, Ruggieri A, Marrero JA, Ioannou GN, Beretta L. Circulating microRNAs in patients with chronic hepatitis C and non-alcoholic fatty liver disease. PLoS ONE 2011; 6(8): e23937CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Celikbilek M, Baskol M, Taheri S, Deniz K, Dogan S, Zararsiz G, Gursoy S, Guven K, Ozbakir O, Dundar M, Yucesoy M. Circulating microRNAs in patients with non-alcoholic fatty liver disease. World J Hepatol 2014; 6(8): 613–620CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Tan Y, Ge G, Pan T, Wen D, Gan J. A pilot study of serum microRNAs panel as potential biomarkers for diagnosis of nonalcoholic fatty liver disease. PLoS ONE 2014; 9(8): e105192CrossRefPubMedPubMedCentralGoogle Scholar

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© Higher Education Press and Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  1. 1.Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for DiabetesShanghai Jiao Tong University Affiliated Sixth People’s HospitalShanghaiChina

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