Table Info

Table 3.

Diagnostic and therapeutic potential of EVs in MAFLD

Cell source	Target cell	EVs markers	Biological effects	References
Hepatocytes	HSCs	TLR-3	Pro-fibrotic response at early stages of liver fibrosis	[67]
Liver (circulating EVs)	Not evaluated	miR-122, miR-192	Increased levels of circulating EVs are associated with the severity of MAFLD	[69]
Hepatocytes	ECs (HUVECs)	VNN-1	FFA-treated hepatocytes released EVs with proangiogenic effects	[72]
ECs	HSCs	FN, integrin	HSC adherence and migration	[51]
HSCs	Not evaluated	Twist 1	Limits the magnitude of the fibrotic response	[54]
CD4⁺ and CD8⁺ T from hepatitis C patient	HSCs	Not evaluated	Induce the upregulation of fibrolytic genes in HSCs	[74]
Activated and quiescent HSCs	Not evaluated	CCN2	HSC activation	[55]
Adipocytes	HepG2 cells	Adipokines	Modulate insulin resistance	[95]
ADSCs	KCs	Not evaluated	Polarize KCs toward Arg-1 M2 phenotype	[75]
AMSCs	KCs	Not evaluated	Decreased number of Kupffer cells and decreased expression of inflammatory genes in NASH rat model	[96]
HLSC	NASH rats	Not evaluated	Improved liver function with downregulation of pro-inflammatory and profibrotic genes	[78]
Human adipose tissue-derived mesenchymal SCs	NASH mice	Not evaluated	Decreased liver fibrosis	[77]
Hepatocytes	Macrophages THP-1 cells	miR-192-5p miR-122-5p	Pro-inflammatory	[47, 49]
Hepatocytes	HSCs and LX2 cells	miR-128-3p miR-192	Pro-fibrotic	[13, 15]
Human umbilical cord-derived mesenchymal SCs	Rat NASH model	miR-627-5p	Improved liver function and reduced lipid accumulation	[92]
Hepatocytes	Adipocytes	miR-130a-3p Let-7e-5p	Increased Glu uptake, lipogenesis, and decreased lipid oxidation	[60]
KCs	Huh7 cells	miRNA-29	Anti-HCV	[97]

AMSCs: amnion-derived mesenchymal SCs

Declarations

Author contributions

ZW contributed to the abstract, sections 1, 2, 5.2, conclusions and Figure 1. MX contributed to the Tables 1, 2 and 3, sections 2 and 3. SSS contributed to sections 1 and 2. MCTA contributed to sections 2, 4, and 5.1. MMA contributed to section 4. JAO contributed to section 4.1 and Table 3. JW contributed to section 3.2 and Table 2. MA, SS, LPB, FGvV, HB, and HM contributed to overall lay-out and content of the manuscript. All authors discussed the results and commented on the manuscript.

Conflicts of interest

The authors declare that they have no known competing financial interests of personal relationships that could have appeared to influence the work reported in this research paper.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

This project is financially supported by the China Scholarship Council (CSC) grant 202008320321 (MX), grant 202006250036 (JW) and grant 201806170085 (ZW), Conacyt grant 795389 (MMA), Colciencias International Scholarship Program grant 783-2017 (JAO), the Abel Tasman Talent Program of the University Medical Center Groningen (MCTA), Dutch Digestive Foundation grant WO 21-03 (SSS; HB; HM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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References

Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64:73–84. [DOI] [PubMed]

Brunt EM. Pathology of nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol. 2010;7:195–203. [DOI] [PubMed]

Lakhani HV, Sharma D, Dodrill MW, Nawab A, Sharma N, Cottrill CL, et al. Phenotypic alteration of hepatocytes in non-alcoholic fatty liver disease. Int J Med Sci. 2018;15:1591–9. [DOI] [PubMed] [PMC]

Kutlu O, Kaleli HN, Ozer E. Molecular pathogenesis of nonalcoholic steatohepatitis- (NASH-) related hepatocellular carcinoma. Can J Gastroenterol Hepatol. 2018;2018:8543763. [DOI] [PubMed] [PMC]

Chargaff E, West R. The biological significance of the thromboplastic protein of blood. J Biol Chem. 1946;166:189–97. [DOI] [PubMed]

Ratajczak J, Miekus K, Kucia M, Zhang J, Reca R, Dvorak P, et al. Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors: evidence for horizontal transfer of mRNA and protein delivery. Leukemia. 2006;20:847–56. [DOI] [PubMed]

Hernández A, Arab JP, Reyes D, Lapitz A, Moshage H, Bañales JM, et al. Extracellular vesicles in NAFLD/ALD: from pathobiology to therapy. Cells. 2020;9:817. [DOI] [PubMed] [PMC]

Hafiane A, Daskalopoulou SS. Extracellular vesicles characteristics and emerging roles in atherosclerotic cardiovascular disease. Metabolism. 2018;85:213–22. [DOI] [PubMed]

Raposo G, Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol. 2013;200:373–83. [DOI] [PubMed] [PMC]

10.

Kornek M, Lynch M, Mehta SH, Lai M, Exley M, Afdhal NH, et al. Circulating microparticles as disease-specific biomarkers of severity of inflammation in patients with hepatitis C or nonalcoholic steatohepatitis. Gastroenterology. 2012;143:448–58. [DOI] [PubMed] [PMC]

11.

Kakazu E, Mauer AS, Yin M, Malhi H. Hepatocytes release ceramide-enriched pro-inflammatory extracellular vesicles in an IRE1α-dependent manner. J Lipid Res. 2016;57:233–45. [DOI] [PubMed] [PMC]

12.

Murakami Y, Toyoda H, Tanahashi T, Tanaka J, Kumada T, Yoshioka Y, et al. Comprehensive miRNA expression analysis in peripheral blood can diagnose liver disease. PLoS One. 2012;7:e48366. [DOI] [PubMed] [PMC]

13.

Lee YS, Kim SY, Ko E, Lee JH, Yi HS, Yoo YJ, et al. Exosomes derived from palmitic acid-treated hepatocytes induce fibrotic activation of hepatic stellate cells. Sci Rep. 2017;7:3710. [DOI] [PubMed] [PMC]

14.

Hirsova P, Ibrahim SH, Krishnan A, Verma VK, Bronk SF, Werneburg NW, et al. Lipid-induced signaling causes release of inflammatory extracellular vesicles from hepatocytes. Gastroenterology. 2016;150:956–67. [DOI] [PubMed] [PMC]

15.

Povero D, Panera N, Eguchi A, Johnson CD, Papouchado BG, de Araujo Horcel L, et al. Lipid-induced hepatocyte-derived extracellular vesicles regulate hepatic stellate cell via microRNAs targeting PPAR-γ. Cell Mol Gastroenterol Hepatol. 2015;1:646–63.e4. [DOI] [PubMed] [PMC]

16.

Doyle LM, Wang MZ. Overview of extracellular vesicles, their origin, composition, purpose, and methods for exosome isolation and analysis. Cells. 2019;8:727. [DOI] [PubMed] [PMC]

17.

Zha QB, Yao YF, Ren ZJ, Li XJ, Tang JH. Extracellular vesicles: an overview of biogenesis, function, and role in breast cancer. Tumour Biol. 2017;39:1010428317691182. [DOI] [PubMed]

18.

Kowal J, Arras G, Colombo M, Jouve M, Morath JP, Primdal-Bengtson B, et al. Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes. Proc Natl Acad Sci U S A. 2016;113:E968–77. [DOI] [PubMed] [PMC]

19.

Akbar N, Azzimato V, Choudhury RP, Aouadi M. Extracellular vesicles in metabolic disease. Diabetologia. 2019;62:2179–87. [DOI] [PubMed] [PMC]

20.

Kanada M, Bachmann MH, Hardy JW, Frimannson DO, Bronsart L, Wang A, et al. Differential fates of biomolecules delivered to target cells via extracellular vesicles. Proc Natl Acad Sci U S A. 2015;112:E1433–42. [DOI] [PubMed] [PMC]

21.

Elzanowska J, Semira C, Costa-Silva B. DNA in extracellular vesicles: biological and clinical aspects. Mol Oncol. 2021;15:1701–14. [DOI] [PubMed] [PMC]

22.

Nabhan JF, Hu R, Oh RS, Cohen SN, Lu Q. Formation and release of arrestin domain-containing protein 1-mediated microvesicles (ARMMs) at plasma membrane by recruitment of TSG101 protein. Proc Natl Acad Sci U S A. 2012;109:4146–51. [DOI] [PubMed] [PMC]

23.

Latifkar A, Hur YH, Sanchez JC, Cerione RA, Antonyak MA. New insights into extracellular vesicle biogenesis and function. J Cell Sci. 2019;132:jcs222406. [DOI] [PubMed] [PMC]

24.

Abels ER, Breakefield XO. Introduction to extracellular vesicles: biogenesis, RNA cargo selection, content, release, and uptake. Cell Mol Neurobiol. 2016;36:301–12. [DOI] [PubMed] [PMC]

25.

Chiaruttini N, Redondo-Morata L, Colom A, Humbert F, Lenz M, Scheuring S, et al. Relaxation of loaded ESCRT-III spiral springs drives membrane deformation. Cell. 2015;163:866–79. [DOI] [PubMed] [PMC]

26.

Muralidharan-Chari V, Clancy JW, Sedgwick A, D’Souza-Schorey C. Microvesicles: mediators of extracellular communication during cancer progression. J Cell Sci. 2010;123:1603–11. [DOI] [PubMed] [PMC]

27.

Morán L, Cubero FJ. Extracellular vesicles in liver disease and beyond. World J Gastroenterol. 2018;24:4519–26. [DOI] [PubMed] [PMC]

28.

Hirsova P, Ibrahim SH, Verma VK, Morton LA, Shah VH, LaRusso NF, et al. Extracellular vesicles in liver pathobiology: small particles with big impact. Hepatology. 2016;64:2219–33. [DOI] [PubMed] [PMC]

29.

Wu D, Zhu H, Wang H. Extracellular vesicles in non-alcoholic fatty liver disease and alcoholic liver disease. Front Physiol. 2021;12:707429. [DOI] [PubMed] [PMC]

30.

Wickman G, Julian L, Olson MF. How apoptotic cells aid in the removal of their own cold dead bodies. Cell Death Differ. 2012;19:735–42. [DOI] [PubMed] [PMC]

31.

Shao H, Im H, Castro CM, Breakefield X, Weissleder R, Lee H. New technologies for analysis of extracellular vesicles. Chem Rev. 2018;118:1917–50. [DOI] [PubMed] [PMC]

32.

Geng Y, Faber KN, de Meijer VE, Blokzijl H, Moshage H. How does hepatic lipid accumulation lead to lipotoxicity in non-alcoholic fatty liver disease? Hepatol Int. 2021;15:21–35. [DOI] [PubMed] [PMC]

33.

Srinivas AN, Suresh D, Santhekadur PK, Suvarna D, Kumar DP. Extracellular vesicles as inflammatory drivers in NAFLD. Front Immunol. 2021;11:627424. [DOI] [PubMed] [PMC]

34.

Newman LA, Sorich MJ, Rowland A. Role of extracellular vesicles in the pathophysiology, diagnosis and tracking of non-alcoholic fatty liver disease. J Clin Med. 2020;9:2032. [DOI] [PubMed] [PMC]

35.

Devhare PB, Ray RB. Extracellular vesicles: novel mediator for cell to cell communications in liver pathogenesis. Mol Aspects Med. 2018;60:115–22. [DOI] [PubMed] [PMC]

36.

Kostallari E, Valainathan S, Biquard L, Shah VH, Rautou PE. Role of extracellular vesicles in liver diseases and their therapeutic potential. Adv Drug Deliv Rev. 2021;175:113816. [DOI] [PubMed]

37.

Hernández A, Geng Y, Sepúlveda R, Solís N, Torres J, Arab JP, et al. Chemical hypoxia induces pro-inflammatory signals in fat-laden hepatocytes and contributes to cellular crosstalk with Kupffer cells through extracellular vesicles. Biochim Biophys Acta Mol Basis Dis. 2020;1866:165753. [DOI] [PubMed]

38.

Guo Q, Furuta K, Lucien F, Gutierrez Sanchez LH, Hirsova P, Krishnan A, et al. Integrin β₁-enriched extracellular vesicles mediate monocyte adhesion and promote liver inflammation in murine NASH. J Hepatol. 2019;71:1193–205. [DOI] [PubMed] [PMC]

39.

Dasgupta D, Nakao Y, Mauer AS, Thompson JM, Sehrawat TS, Liao CY, et al. IRE1A stimulates hepatocyte-derived extracellular vesicles that promote inflammation in mice with steatohepatitis. Gastroenterology. 2020;159:1487–503.e17. Erratum in: Gastroenterology. 2022;162:1363–5. [DOI] [PubMed] [PMC]

40.

Liao CY, Song MJ, Gao Y, Mauer AS, Revzin A, Malhi H. Hepatocyte-derived lipotoxic extracellular vesicle sphingosine 1-phosphate induces macrophage chemotaxis. Front Immunol. 2018;9:2980. [DOI] [PubMed] [PMC]

41.

Garcia-Martinez I, Santoro N, Chen Y, Hoque R, Ouyang X, Caprio S, et al. Hepatocyte mitochondrial DNA drives nonalcoholic steatohepatitis by activation of TLR9. J Clin Invest. 2016;126:859–64. [DOI] [PubMed] [PMC]

42.

Hwang S, He Y, Xiang X, Seo W, Kim SJ, Ma J, et al. Interleukin-22 ameliorates neutrophil-driven nonalcoholic steatohepatitis through multiple targets. Hepatology. 2020;72:412–29. [DOI] [PubMed] [PMC]

43.

Li X, Chen R, Kemper S, Brigstock DR. Dynamic changes in function and proteomic composition of extracellular vesicles from hepatic stellate cells during cellular activation. Cells. 2020;9:290. [DOI] [PubMed] [PMC]

44.

Gao J, Wei B, de Assuncao TM, Liu Z, Hu X, Ibrahim S, et al. Hepatic stellate cell autophagy inhibits extracellular vesicle release to attenuate liver fibrosis. J Hepatol. 2020;73:1144–54. [DOI] [PubMed] [PMC]

45.

Zhang H, Ma Y, Cheng X, Wu D, Huang X, Chen B, et al. Targeting epigenetically maladapted vascular niche alleviates liver fibrosis in nonalcoholic steatohepatitis. Sci Transl Med. 2021;13:eabd1206. [DOI] [PubMed]

46.

Manicardi N, Fernández-Iglesias A, Abad-Jordà L, Royo F, Azkargorta M, Ortega-Ribera M, et al. Transcriptomic profiling of the liver sinusoidal endothelium during cirrhosis reveals stage-specific secretory signature. Cancers (Basel). 2021;13:2688. [DOI] [PubMed] [PMC]

47.

Liu XL, Pan Q, Cao HX, Xin FZ, Zhao ZH, Yang RX, et al. Lipotoxic hepatocyte-derived exosomal microRNA 192-5p activates macrophages through Rictor/Akt/Forkhead box transcription factor O1 signaling in nonalcoholic fatty liver disease. Hepatology. 2020;72:454–69. [DOI] [PubMed]

48.

Liu H, Niu Q, Wang T, Dong H, Bian C. Lipotoxic hepatocytes promote nonalcoholic fatty liver disease progression by delivering microRNA-9-5p and activating macrophages. Int J Biol Sci. 2021;17:3745–59. [DOI] [PubMed] [PMC]

49.

Zhao Z, Zhong L, Li P, He K, Qiu C, Zhao L, et al. Cholesterol impairs hepatocyte lysosomal function causing M1 polarization of macrophages via exosomal miR-122-5p. Exp Cell Res. 2020;387:111738. [DOI] [PubMed]

50.

Tasin FR, Halder D, Mandal C. Possible therapeutic uses of extracellular vesicles for reversion of activated hepatic stellate cells: context and future perspectives. Curr Mol Med. 2022;22:151–64. [DOI] [PubMed]

51.

Wang R, Ding Q, Yaqoob U, de Assuncao TM, Verma VK, Hirsova P, et al. Exosome adherence and internalization by hepatic stellate cells triggers sphingosine 1-phosphate-dependent migration. J Biol Chem. 2015;290:30684–96. [DOI] [PubMed] [PMC]

52.

Hernández A, Reyes D, Geng Y, Arab JP, Cabrera D, Sepulveda R, et al. Extracellular vesicles derived from fat-laden hepatocytes undergoing chemical hypoxia promote a pro-fibrotic phenotype in hepatic stellate cells. Biochim Biophys Acta Mol Basis Dis. 2020;1866:165857. [DOI] [PubMed]

53.

Chen L, Charrier A, Zhou Y, Chen R, Yu B, Agarwal K, et al. Epigenetic regulation of connective tissue growth factor by microRNA-214 delivery in exosomes from mouse or human hepatic stellate cells. Hepatology. 2014;59:1118–29. [DOI] [PubMed] [PMC]

54.

Chen L, Chen R, Kemper S, Charrier A, Brigstock DR. Suppression of fibrogenic signaling in hepatic stellate cells by Twist1-dependent microRNA-214 expression: role of exosomes in horizontal transfer of Twist1. Am J Physiol Gastrointest Liver Physiol. 2015;309:G491–9. [DOI] [PubMed] [PMC]

55.

Charrier A, Chen R, Chen L, Kemper S, Hattori T, Takigawa M, et al. Exosomes mediate intercellular transfer of pro-fibrogenic connective tissue growth factor (CCN2) between hepatic stellate cells, the principal fibrotic cells in the liver. Surgery. 2014;156:548–55. [DOI] [PubMed] [PMC]

56.

Shetty S, Lalor PF, Adams DH. Liver sinusoidal endothelial cells-gatekeepers of hepatic immunity. Nat Rev Gastroenterol Hepatol. 2018;15:555–67. [DOI] [PubMed] [PMC]

57.

Xu M, Wang X, Zou Y, Zhong Y. Key role of liver sinusoidal endothelial cells in liver fibrosis. Biosci Trends. 2017;11:163–8. [DOI] [PubMed]

58.

Yang P, Zhou W, Li C, Zhang M, Jiang Y, Jiang R, et al. Kupffer-cell-expressed transmembrane TNF-α is a major contributor to lipopolysaccharide and D-galactosamine-induced liver injury. Cell Tissue Res. 2016;363:371–83. [DOI] [PubMed]

59.

Wang GX, Pan JY, Wang YJ, Huang TC, Li XF. MiR-640 inhibition alleviates acute liver injury via regulating WNT signaling pathway and LRP1. Eur Rev Med Pharmacol Sci. 2020;24:8988–96. [DOI] [PubMed]

60.

Zhao Y, Zhao MF, Jiang S, Wu J, Liu J, Yuan XW, et al. Liver governs adipose remodelling via extracellular vesicles in response to lipid overload. Nat Commun. 2020;11:719. [DOI] [PubMed] [PMC]

61.

Buratta S, Shimanaka Y, Costanzi E, Ni S, Urbanelli L, Kono N, et al. Lipotoxic stress alters the membrane lipid profile of extracellular vesicles released by Huh-7 hepatocarcinoma cells. Sci Rep. 2021;11:4613. [DOI] [PubMed] [PMC]

62.

Arroyave-Ospina JC, Wu Z, Geng Y, Moshage H. Role of oxidative stress in the pathogenesis of non-alcoholic fatty liver disease: implications for prevention and therapy. Antioxidants (Basel). 2021;10:174. [DOI] [PubMed] [PMC]

63.

Hendrikx T, Binder CJ. Oxidation-specific Epitopes in non-alcoholic fatty liver disease. Front Endocrinol (Lausanne). 2020;11:607011. [DOI] [PubMed] [PMC]

64.

Tsiantoulas D, Perkmann T, Afonyushkin T, Mangold A, Prohaska TA, Papac-Milicevic N, et al. Circulating microparticles carry oxidation-specific epitopes and are recognized by natural IgM antibodies. J Lipid Res. 2015;56:440–8. [DOI] [PubMed] [PMC]

65.

Crewe C, Funcke JB, Li S, Joffin N, Gliniak CM, Ghaben AL, et al. Extracellular vesicle-based interorgan transport of mitochondria from energetically stressed adipocytes. Cell Metab. 2021;33:1853–68.e11. [DOI] [PubMed]

66.

Miura K, Seki E, Ohnishi H, Brenner DA. Role of toll-like receptors and their downstream molecules in the development of nonalcoholic fatty liver disease. Gastroenterol Res Pract. 2010;2010:362847. [DOI] [PubMed] [PMC]

67.

Seo W, Eun HS, Kim SY, Yi HS, Lee YS, Park SH, et al. Exosome-mediated activation of toll-like receptor 3 in stellate cells stimulates interleukin-17 production by γδ T cells in liver fibrosis. Hepatology. 2016;64:616–31. [DOI] [PubMed]

68.

Wan X, Xu C, Yu C, Li Y. Role of NLRP3 inflammasome in the progression of NAFLD to NASH. Can J Gastroenterol Hepatol. 2016;2016:6489012. [DOI] [PubMed] [PMC]

69.

Povero D, Eguchi A, Li H, Johnson CD, Papouchado BG, Wree A, et al. Circulating extracellular vesicles with specific proteome and liver microRNAs are potential biomarkers for liver injury in experimental fatty liver disease. PLoS One. 2014;9:e113651. [DOI] [PubMed] [PMC]

70.

Zuo R, Ye LF, Huang Y, Song ZQ, Wang L, Zhi H, et al. Hepatic small extracellular vesicles promote microvascular endothelial hyperpermeability during NAFLD via novel-miRNA-7. J Nanobiotechnology. 2021;19:396. [DOI] [PubMed] [PMC]

71.

Cannito S, Morello E, Bocca C, Foglia B, Benetti E, Novo E, et al. Microvesicles released from fat-laden cells promote activation of hepatocellular NLRP3 inflammasome: a pro-inflammatory link between lipotoxicity and non-alcoholic steatohepatitis. PLoS One. 2017;12:e0172575. [DOI] [PubMed] [PMC]

72.

Povero D, Eguchi A, Niesman IR, Andronikou N, de Mollerat du Jeu X, Mulya A, et al. Lipid-induced toxicity stimulates hepatocytes to release angiogenic microparticles that require Vanin-1 for uptake by endothelial cells. Sci Signal. 2013;6:ra88. [DOI] [PubMed] [PMC]

73.

Jiang F, Chen Q, Wang W, Ling Y, Yan Y, Xia P. Hepatocyte-derived extracellular vesicles promote endothelial inflammation and atherogenesis via microRNA-1. J Hepatol. 2020;72:156–66. [DOI] [PubMed]

74.

Kornek M, Popov Y, Libermann TA, Afdhal NH, Schuppan D. Human T cell microparticles circulate in blood of hepatitis patients and induce fibrolytic activation of hepatic stellate cells. Hepatology. 2011;53:230–42. [DOI] [PubMed] [PMC]

75.

Zhao H, Shang Q, Pan Z, Bai Y, Li Z, Zhang H, et al. Exosomes from adipose-derived stem cells attenuate adipose inflammation and obesity through polarizing M2 macrophages and Beiging in white adipose tissue. Diabetes. 2018;67:235–47. [DOI] [PubMed]

76.

Nazarie Ignat SR, Gharbia S, Hermenean A, Dinescu S, Costache M. Regenerative potential of mesenchymal stem cells’ (MSCs) secretome for liver fibrosis therapies. Int J Mol Sci. 2021;22:13292. [DOI] [PubMed] [PMC]

77.

Bruno S, Pasquino C, Herrera Sanchez MB, Tapparo M, Figliolini F, Grange C, et al. HLSC-derived extracellular vesicles attenuate liver fibrosis and inflammation in a murine model of non-alcoholic steatohepatitis. Mol Ther. 2020;28:479–89. [DOI] [PubMed] [PMC]

78.

Watanabe T, Tsuchiya A, Takeuchi S, Nojiri S, Yoshida T, Ogawa M, et al. Development of a non-alcoholic steatohepatitis model with rapid accumulation of fibrosis, and its treatment using mesenchymal stem cells and their small extracellular vesicles. Regen Ther. 2020;14:252–61. [DOI] [PubMed] [PMC]

79.

Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281–97. [DOI] [PubMed]

80.

Szabo G, Csak T. Role of microRNAs in NAFLD/NASH. Dig Dis Sci. 2016;61:1314–24. [DOI] [PubMed]

81.

Pérez-García A, Torrecilla-Parra M, Fernández-de Frutos M, Martín-Martín Y, Pardo-Marqués V, Ramírez CM. Posttranscriptional regulation of insulin resistance: implications for metabolic diseases. Biomolecules. 2022;12:208. [DOI] [PubMed] [PMC]

82.

Fluitt MB, Kumari N, Nunlee-Bland G, Nekhai S, Gambhir KK. miRNA-15a, miRNA-15b, and miRNA-499 are reduced in erythrocytes of pre-diabetic African-American adults. Jacobs J Diabetes Endocrinol. 2016;2:014. [PubMed] [PMC]

83.

Bala S, Petrasek J, Mundkur S, Catalano D, Levin I, Ward J, et al. Circulating microRNAs in exosomes indicate hepatocyte injury and inflammation in alcoholic, drug-induced, and inflammatory liver diseases. Hepatology. 2012;56:1946–57. [DOI] [PubMed] [PMC]

84.

Zhang Y, Jia Y, Zheng R, Guo Y, Wang Y, Guo H, et al. Plasma microRNA-122 as a biomarker for viral-, alcohol-, and chemical-related hepatic diseases. Clin Chem. 2010;56:1830–8. [DOI] [PubMed]

85.

Wang K, Zhang S, Marzolf B, Troisch P, Brightman A, Hu Z, et al. Circulating microRNAs, potential biomarkers for drug-induced liver injury. Proc Natl Acad Sci U S A. 2009;106:4402–7. [DOI] [PubMed] [PMC]

86.

Landgraf P, Rusu M, Sheridan R, Sewer A, Iovino N, Aravin A, et al. A mammalian microRNA expression atlas based on small RNA library sequencing. Cell. 2007;129:1401–14. [DOI] [PubMed] [PMC]

87.

Weber JA, Baxter DH, Zhang S, Huang DY, Huang KH, Lee MJ, et al. The microRNA spectrum in 12 body fluids. Clin Chem. 2010;56:1733–41. [DOI] [PubMed] [PMC]

88.

Leidinger P, Backes C, Dahmke IN, Galata V, Huwer H, Stehle I, et al. What makes a blood cell based miRNA expression pattern disease specific?--a miRNome analysis of blood cell subsets in lung cancer patients and healthy controls. Oncotarget. 2014;5:9484–97. [DOI] [PubMed] [PMC]

89.

O’Connell TM, Markunas CA. DNA methylation and microRNA-based biomarkers for risk of type 2 diabetes. Curr Diabetes Rev. 2016;12:20–9. [DOI] [PubMed]

90.

Tay Y, Rinn J, Pandolfi PP. The multilayered complexity of ceRNA crosstalk and competition. Nature. 2014;505:344–52. [DOI] [PubMed] [PMC]

91.

Zhang Z, Moon R, Thorne JL, Moore JB. NAFLD and vitamin D: evidence for intersection of microRNA-regulated pathways. Nutr Res Rev. 2021:1–20. [DOI] [PubMed]

92.

Cheng L, Yu P, Li F, Jiang X, Jiao X, Shen Y, et al. Human umbilical cord-derived mesenchymal stem cell-exosomal miR-627-5p ameliorates non-alcoholic fatty liver disease by repressing FTO expression. Hum Cell. 2021;34:1697–708. [DOI] [PubMed]

93.

El-Derany MO, AbdelHamid SG. Upregulation of miR-96-5p by bone marrow mesenchymal stem cells and their exosomes alleviate non-alcoholic steatohepatitis: emphasis on caspase-2 signaling inhibition. Biochem Pharmacol. 2021;190:114624. [DOI] [PubMed]

94.

Wu J, Dong T, Chen T, Sun J, Luo J, He J, et al. Hepatic exosome-derived miR-130a-3p attenuates glucose intolerance via suppressing PHLPP2 gene in adipocyte. Metabolism. 2020;103:154006. [DOI] [PubMed]

95.

Kranendonk ME, Visseren FL, van Herwaarden JA, Nolte-’t Hoen EN, de Jager W, Wauben MH, et al. Effect of extracellular vesicles of human adipose tissue on insulin signaling in liver and muscle cells. Obesity (Silver Spring). 2014;22:2216–23. [DOI] [PubMed]

96.

Ohara M, Ohnishi S, Hosono H, Yamamoto K, Yuyama K, Nakamura H, et al. Extracellular vesicles from amnion-derived mesenchymal stem cells ameliorate hepatic inflammation and fibrosis in rats. Stem Cells Int. 2018;2018:3212643. [DOI] [PubMed] [PMC]

97.

Zhou Y, Wang X, Sun L, Zhou L, Ma TC, Song L, et al. Toll-like receptor 3-activated macrophages confer anti-HCV activity to hepatocytes through exosomes. FASEB J. 2016;30:4132–40. [DOI] [PubMed] [PMC]