Blood-based novel biomarkers for nonalcoholic steatohepatitis

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References

• 1 Rinella ME. Nonalcoholic fatty liver disease. JAMA 313(22), 2263–2273 (2015). • A systematic review illustrates the pathogenesis and prevalence of nonalcoholic steatohepatitis (NASH) and the role of current diagnostics and liver biopsy for NASH.
  Medline CASGoogle Scholar
• 2 Angulo P. Nonalcoholic fatty liver disease. N. Engl. J. Med. 346(16), 1221–1231 (2002).
  Medline CASGoogle Scholar
• 3 Fassio E, Alvarez E, Domínquez N, Landeira G, Longo C. Natural history of nonalcoholic steatohepatitis: a longitudinal study of repeat liver biopsies. Hepatology 40(4), 820–826 (2004).
  MedlineGoogle Scholar
• 4 Adams LA, Lymp JF, St Sauver J et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 129(1), 113–121 (2005).
  MedlineGoogle Scholar
• 5 Singal AG, Manjunath H, Yopp AC et al. The effect of PNPLA3 on fibrosis progression and development of hepatocellular carcinoma: a meta-analysis. Am. J. Gastroenterol. 109(3), 325–334 (2014).
  Medline CASGoogle Scholar
• 6 Zhu L, Baker SS, Gill C et al. Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH. Hepatology 57(2), 601–609 (2013).
  Medline CASGoogle Scholar
• 7 Masarone M, Federico A, Abenavoli L, Loguercio C, Persico M. Non alcoholic fatty liver: epidemiology and natural history. Rev. Recent Clin. Trials 9(3), 126–133 (2014).
  MedlineGoogle Scholar
• 8 Hu K. Nonalcoholic fatty liver disease: updates in noninvasive diagnosis and correlation with cardiovascular disease. World J. Gastroenterol. 20(24), 7718 (2014).
  MedlineGoogle Scholar
• 9 Vuppalanchi R, Chalasani N. Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: selected practical issues in their evaluation and management. Hepatology 49(1), 306–317 (2009).
  MedlineGoogle Scholar
• 10 Portillo SP, Bril F, Maximos M et al. High prevalence of nonalcoholic fatty liver disease in patients with Type 2 diabetes mellitus and normal plasma aminotransferase levels. J. Clin. Endocr. Metab. 100(6), 2231–2238 (2015).
  MedlineGoogle Scholar
• 11 Schwenzer NF, Springer F, Schraml C, Stefan N, Machann J, Schick F. Non-invasive assessment and quantification of liver steatosis by ultrasound, computed tomography and magnetic resonance. J. Hepatol. 51(3), 433–445 (2009).
  MedlineGoogle Scholar
• 12 Spengler EK, Loomba R. Recommendations for diagnosis, referral for liver biopsy, and treatment of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Mayo Clin. Proc. 90(9), 1233–1246 (2015).
  MedlineGoogle Scholar
• 13 Merriman RB, Ferrell LD, Patti MG et al. Correlation of paired liver biopsies in morbidly obese patients with suspected nonalcoholic fatty liver disease. Hepatology 44(4), 874–880 (2006).
  MedlineGoogle Scholar
• 14 Kamada Y, Ono M, Hyogo H et al. A novel noninvasive diagnostic method for nonalcoholic steatohepatitis using two glycobiomarkers. Hepatology 62(5), 1433–1443 (2015).
  Medline CASGoogle Scholar
• 15 Guha IN, Parkes J, Roderick P et al. Noninvasive markers of fibrosis in nonalcoholic fatty liver disease: validating the European Liver Fibrosis Panel and exploring simple markers. Hepatology 47(2), 455–460 (2008).
  MedlineGoogle Scholar
• 16 Povero D, Feldstein AE. Novel molecular mechanisms in the development of non-alcoholic steatohepatitis. Diabetes Metab. J. 40(1), 1–11 (2016).
  MedlineGoogle Scholar
• 17 Bastati N, Feier D, Wibmer A et al. Noninvasive differentiation of simple steatosis and steatohepatitis by using gadoxetic acid-enhanced MR imaging in patients with nonalcoholic fatty liver disease: a proof-of-concept study1. Radiology 271(3), 739–747 (2014).
  MedlineGoogle Scholar
• 18 Sumida Y. Current status and agenda in the diagnosis of nonalcoholic steatohepatitis in Japan. World J. Hepatol. 2(10), 374 (2010).
  MedlineGoogle Scholar
• 19 Kwok R, Tse YK, Wong GLH et al. Systematic review with meta-analysis: non-invasive assessment of non-alcoholic fatty liver disease-the role of transient elastography and plasma cytokeratin-18 fragments. Aliment. Pharm. Ther. 39(3), 254–269 (2014). • Comprehensively reviews the current noninvasive assessments on NASH and mainly contains physical and clinical methods.
  Medline CASGoogle Scholar
• 20 Loomba R, Quehenberger O, Armando A, Dennis EA. Polyunsaturated fatty acid metabolites as novel lipidomic biomarkers for noninvasive diagnosis of nonalcoholic steatohepatitis. J. Lipid Res. 56(1), 185–192 (2015).
  Medline CASGoogle Scholar
• 21 Tanwar S, Trembling PM, Guha IN et al. Validation of terminal peptide of procollagen III for the detection and assessment of nonalcoholic steatohepatitis in patients with nonalcoholic fatty liver disease. Hepatology 57(1), 103–111 (2013).
  Medline CASGoogle Scholar
• 22 Cao W, Zhao C, Shen C, Wang Y. Cytokeratin 18, alanine aminotransferase, platelets and triglycerides predict the presence of nonalcoholic steatohepatitis. PLoS ONE 8(12), e82092 (2013).
  MedlineGoogle Scholar
• 23 Shimada M, Kawahara H, Ozaki K et al. Usefulness of a combined evaluation of the serum adiponectin level, HOMA-IR, and serum type IV collagen 7S level to predict the early stage of nonalcoholic steatohepatitis. Am. J. Gastroenterol. 102(9), 1931–1938 (2007).
  Medline CASGoogle Scholar
• 24 Younossi ZM, Jarrar M, Nugent C et al. A novel diagnostic biomarker panel for obesity-related nonalcoholic steatohepatitis (NASH). Obes. Surg. 18(11), 1430–1437 (2008).
  MedlineGoogle Scholar
• 25 Becker PP, Rau M, Schmitt J et al. Performance of serum microRNAs -122, -192 and -21 as biomarkers in patients with non-alcoholic steatohepatitis. PLoS ONE 10(11), e142661 (2015).
  Google Scholar
• 26 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 9(8), e105192 (2014).
  MedlineGoogle Scholar
• 27 Polyzos SA, Kountouras J, Slavakis A et al. A novel noninvasive index for nonalcoholic steatohepatitis: a pilot study. Biomarkers 18(7), 607–613 (2013).
  Medline CASGoogle Scholar
• 28 Feldstein AE, Wieckowska A, Lopez AR, Liu Y, Zein NN, McCullough AJ. Cytokeratin-18 fragment levels as noninvasive biomarkers for nonalcoholic steatohepatitis: a multicenter validation study. Hepatology 50(4), 1072–1078 (2009).
  Medline CASGoogle Scholar
• 29 Yilmaz Y. Biomarkers for early detection of non-alcoholic steatohepatitis: implications for drug development and clinical trials. Curr. Drug Targets 14(11), 1357–1366 (2013).
  Medline CASGoogle Scholar
• 30 Polyzos SA, Kountouras J, Papatheodorou A et al. Adipocytokines and cytokeratin-18 in patients with nonalcoholic fatty liver disease: introduction of CHA index. Ann. Hepatol. 12(5), 749–757 (2013).
  Medline CASGoogle Scholar
• 31 Kawanaka M, Nishino K, Nakamura J et al. Correlation between serum cytokeratin-18 and the progression or regression of non-alcoholic fatty liver disease. Ann. Hepatol. 14(6), 837–844 (2015).
  MedlineGoogle Scholar
• 32 Shen J, Chan HL, Wong GL et al. Non-invasive diagnosis of non-alcoholic steatohepatitis by combined serum biomarkers. J. Hepatol. 56(6), 1363–1370 (2012).
  Medline CASGoogle Scholar
• 33 Yang M, Xu D, Liu Y et al. Combined serum biomarkers in non-invasive diagnosis of non-alcoholic steatohepatitis. PLoS ONE 10(6), e131664 (2015).
  Google Scholar
• 34 Cusi K, Chang Z, Harrison S et al. Limited value of plasma cytokeratin-18 as a biomarker for NASH and fibrosis in patients with non-alcoholic fatty liver disease. J. Hepatol. 60(1), 167–174 (2014).
  Medline CASGoogle Scholar
• 35 Okuyama N, Ide Y, Nakano M et al. Fucosylated haptoglobin is a novel marker for pancreatic cancer: a detailed analysis of the oligosaccharide structure and a possible mechanism for fucosylation. Int. J. Cancer 118(11), 2803–2808 (2006).
  Medline CASGoogle Scholar
• 36 Yoon Y, Török N, Krueger E, Oswald B, McNiven MA. Ethanol-induced alterations of the microtubule cytoskeleton in hepatocytes. Am. J. Physiol. G757–G765 (1998).
  MedlineGoogle Scholar
• 37 Kamada Y, Akita M, Takeda Y et al. Serum fucosylated haptoglobin as a novel diagnostic biomarker for predicting hepatocyte ballooning and nonalcoholic steatohepatitis. PLoS ONE 8(6), e66328 (2013).
  Medline CASGoogle Scholar
• 38 Kamada Y, Fujii H, Fujii H et al. Serum Mac-2 binding protein levels as a novel diagnostic biomarker for prediction of disease severity and nonalcoholic steatohepatitis. Proteomics Clin. Appl. 7(9–10), 648–656 (2013).
  Medline CASGoogle Scholar
• 39 Stojsavljević S. Adipokines and proinflammatory cytokines, the key mediators in the pathogenesis of nonalcoholic fatty liver disease. World J. Gastroenterol. 20(48), 18070 (2014).
  Medline CASGoogle Scholar
• 40 Abenavoli L, Peta V. Role of adipokines and cytokines in non-alcoholic fatty liver disease. Rev. Recent Clin. Trials 9(3), 134–140 (2014).
  Medline CASGoogle Scholar
• 41 Polyzos SA, Kountouras J, Mantzoros CS. Adipokines in nonalcoholic fatty liver disease. Metabolism 65(8), 1062–1079 (2016).
  Medline CASGoogle Scholar
• 42 Yoda-Murakami M, Taniguchi M, Takahashi K et al. Change in expression of GBP28/adiponectin in carbon tetrachloride-administrated mouse liver. Biochem. Biophys. Res. Commun. 285(2), 372–377 (2001).
  Medline CASGoogle Scholar
• 43 Yamauchi T, Kamon J, Ito Y et al. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature 423(6941), 762–769 (2003).
  Medline CASGoogle Scholar
• 44 Gatselis NK, Ntaios G, Makaritsis K, Dalekos GN. Adiponectin: a key playmaker adipocytokine in non-alcoholic fatty liver disease. Clin. Exp. Med. 14(2), 121–131 (2014).
  Medline CASGoogle Scholar
• 45 Hui JM, Hodge A, Farrell GC, Kench JG, Kriketos A, George J. Beyond insulin resistance in NASH: TNF-alpha or adiponectin? Hepatology 40(1), 46–54 (2004).
  Medline CASGoogle Scholar
• 46 van der Poorten D, Samer CF, Ramezani-Moghadam M et al. Hepatic fat loss in advanced nonalcoholic steatohepatitis: are alterations in serum adiponectin the cause? Hepatology 57(6), 2180–2188 (2013).
  Medline CASGoogle Scholar
• 47 Polyzos SA, Toulis KA, Goulis DG, Zavos C, Kountouras J. Serum total adiponectin in nonalcoholic fatty liver disease: a systematic review and meta-analysis. Metabolism 60(3), 313–326 (2011).
  Medline CASGoogle Scholar
• 48 Fukushima J, Kamada Y, Matsumoto H et al. Adiponectin prevents progression of steatohepatitis in mice by regulating oxidative stress and Kupffer cell phenotype polarization. Hepatol. Res. 39(7), 724–738 (2009).
  Medline CASGoogle Scholar
• 49 Ma H, You G, Zhang X et al. A novel role of globular adiponectin in treatment with HFD/STZ induced T2DM combined with NAFLD rats. Sci. World J. 2014, 1–7 (2014).
  Google Scholar
• 50 Jamali R, Arj A, Razavizade M, Aarabi MH. Prediction of nonalcoholic fatty liver disease via a novel panel of serum adipokines. Medicine 95(5), e2630 (2016).
  Medline CASGoogle Scholar
• 51 Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature 372(6505), 425–432 (1994).
  Medline CASGoogle Scholar
• 52 Kelesidis T, Kelesidis I, Chou S, Mantzoros CS. Narrative review: the role of leptin in human physiology: emerging clinical applications. Ann. Intern. Med. 152(2), 93–100 (2010).
  MedlineGoogle Scholar
• 53 Farooqi IS, Matarese G, Lord GM et al. Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. J. Clin. Invest. 110(8), 1093–1103 (2002).
  Medline CASGoogle Scholar
• 54 Dalamaga M, Chou SH, Shields K, Papageorgiou P, Polyzos SA, Mantzoros CS. Leptin at the intersection of neuroendocrinology and metabolism: current evidence and therapeutic perspectives. Cell Metab. 18(1), 29–42 (2013).
  Medline CASGoogle Scholar
• 55 Fantuzzi G, Faggioni R. Leptin in the regulation of immunity, inflammation, and hematopoiesis. J. Leukoc. Biol. 68(4), 437–446 (2000).
  Medline CASGoogle Scholar
• 56 Polyzos SA, Aronis KN, Kountouras J, Raptis DD, Vasiloglou MF, Mantzoros CS. Circulating leptin in non-alcoholic fatty liver disease: a systematic review and meta-analysis. Diabetologia 59(1), 30–43 (2016).
  Medline CASGoogle Scholar
• 57 Zelber-Sagi S, Lotan R, Shlomai A et al. Predictors for incidence and remission of NAFLD in the general population during a seven-year prospective follow-up. J. Hepatol. 56(5), 1145–1151 (2012).
  MedlineGoogle Scholar
• 58 Curat CA, Wegner V, Sengenes C et al. Macrophages in human visceral adipose tissue: increased accumulation in obesity and a source of resistin and visfatin. Diabetologia 49(4), 744–747 (2006).
  Medline CASGoogle Scholar
• 59 Revollo JR, Korner A, Mills KF et al. Nampt/PBEF/Visfatin regulates insulin secretion in beta cells as a systemic NAD biosynthetic enzyme. Cell Metab. 6(5), 363–375 (2007).
  Medline CASGoogle Scholar
• 60 Moschen AR, Gerner RR, Tilg H. Pre-B cell colony enhancing factor/NAMPT/visfatin in inflammation and obesity-related disorders. Curr. Pharm. Des. 16(17), 1913–1920 (2010).
  Medline CASGoogle Scholar
• 61 Genc H, Dogru T, Kara M et al. Association of plasma visfatin with hepatic and systemic inflammation in nonalcoholic fatty liver disease. Ann. Hepatol. 12(4), 548–555 (2013).
  MedlineGoogle Scholar
• 62 Jarrar MH, Baranova A, Collantes R et al. Adipokines and cytokines in non-alcoholic fatty liver disease. Aliment. Pharm. Ther. 27(5), 412–421 (2008).
  Medline CASGoogle Scholar
• 63 Kloting N, Graham TE, Berndt J et al. Serum retinol-binding protein is more highly expressed in visceral than in subcutaneous adipose tissue and is a marker of intra-abdominal fat mass. Cell Metab. 6(1), 79–87 (2007).
  MedlineGoogle Scholar
• 64 Muenzner M, Tuvia N, Deutschmann C et al. Retinol-binding protein 4 and its membrane receptor STRA6 control adipogenesis by regulating cellular retinoid homeostasis and retinoic acid receptor alpha activity. Mol. Cell. Biol. 33(20), 4068–4082 (2013).
  Medline CASGoogle Scholar
• 65 Yang Q, Graham TE, Mody N et al. Serum retinol binding protein 4 contributes to insulin resistance in obesity and Type 2 diabetes. Nature 436(7049), 356–362 (2005).
  Medline CASGoogle Scholar
• 66 Terra X, Auguet T, Broch M et al. Retinol binding protein-4 circulating levels were higher in nonalcoholic fatty liver disease vs. histologically normal liver from morbidly obese women. Obesity (Silver Spring) 21(1), 170–177 (2012).
  Google Scholar
• 67 Milner KL, van der Poorten D, Xu A et al. Adipocyte fatty acid binding protein levels relate to inflammation and fibrosis in nonalcoholic fatty liver disease. Hepatology 49(6), 1926–1934 (2009).
  Medline CASGoogle Scholar
• 68 Kashyap SR, Diab DL, Baker AR et al. Triglyceride levels and not adipokine concentrations are closely related to severity of nonalcoholic fatty liver disease in an obesity surgery cohort. Obesity (Silver Spring) 17(9), 1696–1701 (2009).
  Medline CASGoogle Scholar
• 69 Alkhouri N, Lopez R, Berk M, Feldstein AE. Serum retinol-binding protein 4 levels in patients with nonalcoholic fatty liver disease. J. Clin. Gastroenterol. 43(10), 985–989 (2009).
  Medline CASGoogle Scholar
• 70 Nobili V, Alkhouri N, Alisi A et al. Retinol-binding protein 4: a promising circulating marker of liver damage in pediatric nonalcoholic fatty liver disease. Clin. Gastroenterol. Hepatol. 7(5), 575–579 (2009).
  Medline CASGoogle Scholar
• 71 Ikonen E. Cellular cholesterol trafficking and compartmentalization. Nat. Rev. Mol. Cell. Biol. 9(2), 125–138 (2008).
  Medline CASGoogle Scholar
• 72 Puri P, Wiest MM, Cheung O et al. The plasma lipidomic signature of nonalcoholic steatohepatitis. Hepatology 50(6), 1827–1838 (2009).
  Medline CASGoogle Scholar
• 73 Van Rooyen DM, Larter CZ, Haigh WG et al. Hepatic free cholesterol accumulates in obese, diabetic mice and causes nonalcoholic steatohepatitis. Gastroenterology 141(4), 1393–1403 (2011).
  Medline CASGoogle Scholar
• 74 Caballero F, Fernandez A, De Lacy AM, Fernandez-Checa JC, Caballeria J, Garcia-Ruiz C. Enhanced free cholesterol, SREBP-2 and StAR expression in human NASH. J. Hepatol. 50(4), 789–796 (2009).
  Medline CASGoogle Scholar
• 75 Min HK, Kapoor A, Fuchs M et al. Increased hepatic synthesis and dysregulation of cholesterol metabolism is associated with the severity of nonalcoholic fatty liver disease. Cell Metab. 15(5), 665–674 (2012).
  Medline CASGoogle Scholar
• 76 Musso G, Gambino R, Cassader M. Cholesterol metabolism and the pathogenesis of non-alcoholic steatohepatitis. Prog. Lipid Res. 52(1), 175–191 (2013).
  Medline CASGoogle Scholar
• 77 Walenbergh SM, Shiri-Sverdlov R. Cholesterol is a significant risk factor for non-alcoholic steatohepatitis. Expert Rev. Gastroenterol. Hepatol. 9(11), 1343–1346 (2015).
  Medline CASGoogle Scholar
• 78 Arguello G, Balboa E, Arrese M, Zanlungo S. Recent insights on the role of cholesterol in non-alcoholic fatty liver disease. Biochim. Biophys. Acta 1852(9), 1765–1778 (2015).
  Medline CASGoogle Scholar
• 79 Davidson MH, Voogt J, Luchoomun J et al. Inhibition of intestinal cholesterol absorption with ezetimibe increases components of reverse cholesterol transport in humans. Atherosclerosis 230(2), 322–329 (2013).
  Medline CASGoogle Scholar
• 80 Boden G. Fatty acid-induced inflammation and insulin resistance in skeletal muscle and liver. Curr. Diab. Rep. 6(3), 177–181 (2006).
  Medline CASGoogle Scholar
• 81 Neuschwander-Tetri BA. Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites. Hepatology 52(2), 774–788 (2010).
  MedlineGoogle Scholar
• 82 Hafizi ABM, Kian KC, Wan HW, Sarmidi MR, Yaakob H, Zaman HH. Mitochondrial dysfunction as a central event for mechanisms underlying insulin resistance: the roles of long chain fatty acids. Diabetes Metab. Res. Rev. 31(5), 453–475 (2015).
  MedlineGoogle Scholar
• 83 de Almeida IT, Cortez-Pinto H, Fidalgo G, Rodrigues D, Camilo ME. Plasma total and free fatty acids composition in human non-alcoholic steatohepatitis. Clin. Nutr. 21(3), 219–223 (2002).
  MedlineGoogle Scholar
• 84 Walle P, Takkunen M, Mannisto V et al. Fatty acid metabolism is altered in non-alcoholic steatohepatitis independent of obesity. Metabolism 65(5), 655–666 (2016).
  Medline CASGoogle Scholar
• 85 Leamy AK, Egnatchik RA, Young JD. Molecular mechanisms and the role of saturated fatty acids in the progression of non-alcoholic fatty liver disease. Prog. Lipid Res. 52(1), 165–174 (2013).
  Medline CASGoogle Scholar
• 86 Kawano Y, Cohen DE. Mechanisms of hepatic triglyceride accumulation in non-alcoholic fatty liver disease. J. Gastroenterol. 48(4), 434–441 (2013).
  Medline CASGoogle Scholar
• 87 Puri P, Baillie RA, Wiest MM et al. A lipidomic analysis of nonalcoholic fatty liver disease. Hepatology 46(4), 1081–1090 (2007).
  Medline CASGoogle Scholar
• 88 Gorden DL, Ivanova PT, Myers DS et al. Increased diacylglycerols characterize hepatic lipid changes in progression of human nonalcoholic fatty liver disease; comparison to a murine model. PLoS ONE 6(8), e22775 (2011).
  Medline CASGoogle Scholar
• 89 Martel C, Esposti DD, Bouchet A, Brenner C, Lemoine A. Non-alcoholic steatohepatitis: new insights from OMICS studies. Curr. Pharm. Biotechnol. 13(5), 726–735 (2012).
  Medline CASGoogle Scholar
• 90 Yamaguchi K, Yang L, McCall S et al. Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis. Hepatology 45(6), 1366–1374 (2007).
  Medline CASGoogle Scholar
• 91 Kawano Y, Nishiumi S, Saito M, Yano Y, Azuma T, Yoshida M. Identification of lipid species linked to the progression of non-alcoholic fatty liver disease. Curr. Drug Targets 16(12), 1293–1300 (2015).
  Medline CASGoogle Scholar
• 92 Ambros V. The functions of animal microRNAs. Nature 431(7006), 350–355 (2004).
  Medline CASGoogle Scholar
• 93 Selbach M, Schwanhäusser B, Thierfelder N, Fang Z, Khanin R, Rajewsky N. Widespread changes in protein synthesis induced by microRNAs. Nature 455(7209), 58–63 (2008).
  Medline CASGoogle Scholar
• 94 Mitchell PS, Parkin RK, Kroh EM et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc. Natl Acad. Sci. USA 105(30), 10513–10518 (2008).
  Medline CASGoogle Scholar
• 95 Cheung O, Puri P, Eicken C et al. Nonalcoholic steatohepatitis is associated with altered hepatic microRNA expression. Hepatology 48(6), 1810–1820 (2008).
  Medline CASGoogle Scholar
• 96 Reddy JK. Lipid metabolism and liver inflammation. II. Fatty liver disease and fatty acid oxidation. AJP 290(5), G852–G858 (2005).
  Google Scholar
• 97 Pirola CJ, Fernández Gianotti T, Castaño GO et al. Circulating microRNA signature in non-alcoholic fatty liver disease: from serum non-coding RNAs to liver histology and disease pathogenesis. Gut 64(5), 800–812 (2015). • A case–control study that provides novel insights into the association of circulating miRNAs with the pathogenesis of NASH.
  Medline CASGoogle Scholar
• 98 Amacher DE. Progress in the search for circulating biomarkers of nonalcoholic fatty liver disease. Biomarkers 19(7), 541–552 (2014).
  Medline CASGoogle Scholar
• 99 Jin X, Ye YF, Chen SH, Yu CH, Liu J, Li YM. microRNA expression pattern in different stages of nonalcoholic fatty liver disease. Dig. Liver Dis. 41(4), 289–297 (2009).
  Medline CASGoogle Scholar
• 100 Alisi A, Da SL, Bruscalupi G et al. Mirnome analysis reveals novel molecular determinants in the pathogenesis of diet-induced nonalcoholic fatty liver disease. Lab. Invest. 91(2), 283–293 (2011).
  Medline CASGoogle Scholar
• 101 Fernández-Hernando C, Suárez Y, Rayner KJ, Moore KJ. microRNAs in lipid metabolism. Curr. Opin. Lipidol. 22(2), 86–92 (2011).
  Medline CASGoogle Scholar
• 102 Chang J, Nicolas E, Marks S et al. miR-122, a mammalian liver-specific microRNA, is processed from hcr mRNA and may downregulate the high affinity cationicamino acid transporter CAT-1. RNA Biol. 1(2), 106–113 (2004).
  Medline CASGoogle Scholar
• 103 Cheung O, Sanyal AJ. Role of microRNAs in non-alcoholic steatohepatitis. Curr. Pharm. Design 16(17), 1952–1957 (2010).
  Medline CASGoogle Scholar
• 104 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. 34(6), 726–732 (2014).
  Medline CASGoogle Scholar
• 105 Miyaaki H, Ichikawa T, Kamo Y et al. Significance of serum and hepatic microRNA-122 levels in patients with non-alcoholic fatty liver disease. Liver Int. 34(7), e302–e307 (2014).
  Medline CASGoogle Scholar
• 106 Yamada H, Suzuki K, Ichino N et al. Associations between circulating microRNAs (miR-21, miR-34a, miR-122 and miR-451) and non-alcoholic fatty liver. Clin. Chim. Acta 424, 99–103 (2013).
  Medline CASGoogle Scholar
• 107 Zaborowski MP, Balaj L, Breakefield XO, Lai CP. Extracellular vesicles: composition, biological relevance, and methods of study. BioScience 65(8), 783–797 (2015).
  MedlineGoogle Scholar
• 108 Yáñez-Mó M, Siljander RM, Andreu Z et al. Biological properties of extracellular vesicles and their physiological functions. J. Extracell. Vesicles 4, 1–60 (2015).
  Google Scholar
• 109 Tkach M, Thery C. Communication by extracellular vesicles: where we are and where we need to go. Cell 164(6), 1226–1232 (2016).
  Medline CASGoogle Scholar
• 110 Shelke GV, Lässer C, Gho YS, Lötvall J. Importance of exosome depletion protocols to eliminate functional and RNA-containing extracellular vesicles from fetal bovine serum. J. Extracell. Vesicles 3, 1–8 (2014).
  Google Scholar
• 111 Sato K, Meng F, Glaser S, Alpini G. Exosomes in liver pathology. J. Hepatol. 65(1), 213–221 (2016).
  Medline CASGoogle Scholar
• 112 Povero D, Eguchi A, Niesman IR et al. Lipid-induced toxicity stimulates hepatocytes to release angiogenic microparticles that require vanin-1 for uptake by endothelial cells. Sci. Signal. 6(296), a88 (2013).
  Google Scholar
• 113 Kornek M, Lynch M, Mehta SH et al. Circulating microparticles as disease-specific biomarkers of severity of inflammation in patients with hepatitis C or nonalcoholic steatohepatitis. Gastroenterology 143(2), 448–458 (2012).
  Medline CASGoogle Scholar
• 114 Povero D, Eguchi A, Li H et al. Circulating extracellular vesicles with specific proteome and liver microRNAs are potential biomarkers for liver injury in experimental fatty liver disease. PLoS ONE 9(12), e113651 (2014).
  MedlineGoogle Scholar
• 115 Hirsova P, Ibrahim SH, Krishnan A et al. Lipid-induced signaling causes release of inflammatory extracellular vesicles from hepatocytes. Gastroenterology 150(4), 956–967 (2016).
  Medline CASGoogle Scholar
• 116 Cheung O, Puri P, Eicken C et al. Nonalcoholic steatohepatitis is associated with altered hepatic microRNA expression. Hepatology 48(6), 1810–1820 (2008).
  Medline CASGoogle Scholar
• 117 Cheng L, Sharples RA, Scicluna BJ, Hill AF. Exosomes provide a protective and enriched source of miRNA for biomarker profiling compared with intracellular and cell-free blood. J. Extracell. Vesicles 3(1), 17–27 (2013).
  Google Scholar
• 118 Bala S, Petrasek J, Mundkur S et al. Circulating microRNAs in exosomes indicate hepatocyte injury and inflammation in alcoholic, drug-induced, and inflammatory liver diseases. Hepatology 56(5), 1946–1957 (2012).
  Medline CASGoogle Scholar
• 119 Conde-Vancells J, Rodriguez-Suarez E, Gonzalez E et al. Candidate biomarkers in exosome-like vesicles purified from rat and mouse urine samples. Proteomics Clin. Appl. 4(4), 416–425 (2010).
  Medline CASGoogle Scholar
• 120 Heeringa M, Hastings A, Yamazaki S, de Koning P. Serum biomarkers in nonalcoholic steatohepatitis: value for assessing drug effects? Biomark. Med. 6(6), 743–757 (2012). • A previous analysis of the drug value of circulating biomarkers in NASH.
  CASGoogle Scholar
• 121 Armutcu F, Akyol S, Ucar F, Erdogan S, Akyol O. Markers in nonalcoholic steatohepatitis. Adv. Clin. Chem. 61, 67–125 (2013).
  Medline CASGoogle Scholar
• 122 Sodhi K, Bracero L. Role of serum biomarkers in early detection of non-alcoholic steatohepatitis and fibrosis in west Virginian children. J. Clin. Cell. Immunol. 7(1), 393 (2016).
  MedlineGoogle Scholar
• 123 Tanaka N, Takahashi S, Zhang Y et al. Role of fibroblast growth factor 21 in the early stage of NASH induced by methionine- and choline-deficient diet. Biochim. Biophys. Acta 1852(7), 1242–1252 (2015).
  Medline CASGoogle Scholar
• 124 Liu J, Xu Y, Hu Y, Wang G. The role of fibroblast growth factor 21 in the pathogenesis of non-alcoholic fatty liver disease and implications for therapy. Metabolism 64(3), 380–390 (2015).
  Medline CASGoogle Scholar
• 125 Adams LA. Biomarkers of liver fibrosis. J. Gastroenterol. Hepatol. 26(5), 802–809 (2011).
  MedlineGoogle Scholar
• 126 Chernyak OO, Sentsova TB, Vorozhko IV, Tutelyan VA, Gapparova KM, Isakov VA. [Genomic, proteomic and metabolomic predictors of nonalcoholic fatty liver disease development in obese patients. Part I]. Voprosy Pitaniia 84(4), 18–24 (2015). • Analyzes diverse molecules by genomic, proteomic and metabolomic techniques and may enhance the performance of predictors of nonalcoholic fatty liver disease.
  Medline CASGoogle Scholar
• 127 Paredes AH, Torres DM, Harrison SA. Treatment of nonalcoholic fatty liver disease: role of dietary modification and exercise. Clin. Liver Dis. 1(4), 117–118 (2012). • Guidelines and recommendations for NASH patients to help improve their health.
  Google Scholar
• 128 Heilig M, Leggio L. What the alcohol doctor ordered from the neuroscientist: theragnostic biomarkers for personalized treatments. Prog. Brain Res. 224(1), 69–77 (2015).
  Google Scholar
• 129 Sanyal AJ, Friedman SL, McCullough AJ, Dimick-Santos L. Challenges and opportunities in drug and biomarker development for nonalcoholic steatohepatitis: findings and recommendations from an American Association for the Study of Liver Diseases – U.S. Food and Drug Administration Joint Workshop. Hepatology 61(4), 1392–1405 (2015).
  MedlineGoogle Scholar
• 130 Anstee QM, Concas D, Kudo H et al. Impact of pan-caspase inhibition in animal models of established steatosis and non-alcoholic steatohepatitis. J. Hepatol. 53(3), 542–550 (2010).
  Medline CASGoogle Scholar
• 131 Sanyal AJ, Brunt EM, Kleiner DE et al. End points and clinical trial design for nonalcoholic steatohepatitis. Hepatology 54(1), 344–353 (2011).
  MedlineGoogle Scholar