{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T01:41:47Z","timestamp":1790041307352,"version":"4.0.1"},"reference-count":110,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2020,9,13]],"date-time":"2020-09-13T00:00:00Z","timestamp":1599955200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1R15HL150721"],"award-info":[{"award-number":["1R15HL150721"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>(1) Background: Nonalcoholic fatty liver disease (NAFLD) is primarily characterized by the presence of fatty liver, hepatic inflammation and fibrogenesis eventually leading to nonalcoholic steatohepatitis (NASH) or cirrhosis. Obesity and diabetes are common risk factors associated with the development and progression of NAFLD, with one of the highest prevalence of these diseased conditions in the West Virginia population. Currently, the diagnosis of NAFLD is limited to radiologic studies and biopsies, which are not cost-effective and highly invasive. Hence, this study aimed to develop a panel and assess the progressive levels of circulatory biomarkers and miRNA expression in patients at risk for progression to NASH to allow early intervention strategies. (2) Methods: In total, 62 female patients were enrolled and blood samples were collected after 8\u201310 h of fasting. Computed tomography was performed on abdomen\/pelvis following IV contrast administration. The patients were divided into the following groups: Healthy subjects with normal BMI and normal fasting blood glucose (Control, n = 20), Obese with high BMI and normal fasting blood glucose (Obese, n = 20) and Obese with high fasting blood glucose (Obese + DM, n = 22). Based on findings from CT, another subset was created from Obese + DM group with patients who showed signs of fatty liver infiltration (Obese + DM(FI), n = 10). ELISA was performed for measurement of plasma biomarkers and RT-PCR was performed for circulating miRNA expression. (3) Results: Our results show significantly increased levels of plasma IL-6, Leptin and FABP-1, while significantly decreased level of adiponectin in Obese, Obese + DM and Obese + DM(FI) group, as compared to healthy controls. The level of CK-18 was significantly increased in Obese + DM(FI) group as compared to control. Subsequently, the expression of miR-122, miR-34a, miR-375, miR-16 and miR-21 was significantly increased in Obese + DM and Obese + DM(FI) group as compared to healthy control. Our results also show distinct correlation of IL-6, FABP-1 and adiponectin levels with the expression of miRNAs in relation to the extent of NAFLD progression. (4) Conclusion: Our results support the clinical application of these biomarkers and miRNAs in monitoring the progression of NAFLD, suggesting a more advanced diagnostic potential of this panel than conventional methods. This panel may provide an appropriate method for early prognosis and management of NAFLD and subsequent adverse hepatic pathophysiology, potentially reducing the disease burden on the West Virginia population.<\/jats:p>","DOI":"10.3390\/ijms21186698","type":"journal-article","created":{"date-parts":[[2020,9,13]],"date-time":"2020-09-13T21:11:32Z","timestamp":1600031492000},"page":"6698","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Predicting Nonalcoholic Fatty Liver Disease through a Panel of Plasma Biomarkers and MicroRNAs in Female West Virginia Population"],"prefix":"10.3390","volume":"21","author":[{"given":"Sneha S.","family":"Pillai","sequence":"first","affiliation":[{"name":"Departments of Surgery and Biomedical Sciences, Marshall University Joan C. Edwards School of Medicine, Huntington, WV 25701, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hari Vishal","family":"Lakhani","sequence":"additional","affiliation":[{"name":"Departments of Surgery and Biomedical Sciences, Marshall University Joan C. Edwards School of Medicine, Huntington, WV 25701, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mishghan","family":"Zehra","sequence":"additional","affiliation":[{"name":"Departments of Surgery and Biomedical Sciences, Marshall University Joan C. Edwards School of Medicine, Huntington, WV 25701, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayan","family":"Wang","sequence":"additional","affiliation":[{"name":"Departments of Surgery and Biomedical Sciences, Marshall University Joan C. Edwards School of Medicine, Huntington, WV 25701, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anum","family":"Dilip","sequence":"additional","affiliation":[{"name":"Departments of Surgery and Biomedical Sciences, Marshall University Joan C. Edwards School of Medicine, Huntington, WV 25701, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nitin","family":"Puri","sequence":"additional","affiliation":[{"name":"Departments of Biomedical Sciences and Medical Education, Marshall University Joan C. Edwards School of Medicine, Huntington, WV 25701, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen","family":"O\u2019Hanlon","sequence":"additional","affiliation":[{"name":"Departments of Family Medicine, Marshall University Joan C. Edwards School of Medicine, Huntington, WV 25701, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1179-2985","authenticated-orcid":false,"given":"Komal","family":"Sodhi","sequence":"additional","affiliation":[{"name":"Departments of Surgery and Biomedical Sciences, Marshall University Joan C. Edwards School of Medicine, Huntington, WV 25701, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,9,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Lonardo, A., and Targher, G. (2017). NAFLD: Is there anything new under the sun?. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18091955"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"485","DOI":"10.3389\/fendo.2018.00485","article-title":"Pathogenesis of nonalcoholic steatohepatitis and hormone-based therapeutic approaches","volume":"9","author":"Kim","year":"2018","journal-title":"Front. Endocrinol."},{"key":"ref_3","first-page":"14","article-title":"Health and Economic Burden of Nonalcoholic Fatty Liver Disease in the United States and Its Impact on Veterans","volume":"36","author":"Shetty","year":"2019","journal-title":"Fed. Pract."},{"key":"ref_4","first-page":"305","article-title":"Hepatitis C virus infection and nonalcoholic steatohepatitis","volume":"8","author":"Patel","year":"2012","journal-title":"Gastroenterol. Hepatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4172\/2155-9899.1000523","article-title":"Investigating molecular connections of non-alcoholic fatty liver disease with associated pathological conditions in west Virginia for biomarker analysis","volume":"8","author":"Sharma","year":"2017","journal-title":"J. Clin. Cell. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e330","DOI":"10.1016\/j.orcp.2013.05.004","article-title":"Increased oxidative stress in obesity: Implications for metabolic syndrome, diabetes, hypertension, dyslipidemia, atherosclerosis, and cancer","volume":"7","author":"Matsuda","year":"2013","journal-title":"Obes. Res. Clin. Pract."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1089\/met.2015.0095","article-title":"Obesity, oxidative stress, adipose tissue dysfunction, and the associated health risks: Causes and therapeutic strategies","volume":"13","author":"Manna","year":"2015","journal-title":"Metab. Syndr. Relat. Disord."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.freeradbiomed.2020.02.025","article-title":"Role of oxidative stress in the pathogenesis of nonalcoholic fatty liver disease","volume":"152","author":"Chen","year":"2020","journal-title":"Free Radic. Biol. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"R733","DOI":"10.1152\/ajpregu.00153.2019","article-title":"Loss of hepatic PPARalpha promotes inflammation and serum hyperlipidemia in diet-induced obesity","volume":"317","author":"Stec","year":"2019","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"149","DOI":"10.5009\/gnl.2012.6.2.149","article-title":"NASH is an inflammatory disorder: Pathogenic, prognostic and therapeutic implications","volume":"6","author":"Farrell","year":"2012","journal-title":"Gut Liver"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Ore, A., and Akinloye, O.A. (2019). Oxidative stress and antioxidant biomarkers in clinical and experimental models of non-alcoholic fatty liver disease. Medicina, 55.","DOI":"10.3390\/medicina55020026"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1002\/oby.20559","article-title":"Increased HO-1 levels ameliorate fatty liver development through a reduction of heme and recruitment of FGF21","volume":"22","author":"Hinds","year":"2014","journal-title":"Obesity"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e146","DOI":"10.1038\/nutd.2014.43","article-title":"Determining the association between adipokine expression in multiple tissues and phenotypic features of non-alcoholic fatty liver disease in obesity","volume":"5","author":"Wolfs","year":"2015","journal-title":"Nutr. Diabetes"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.tem.2018.01.002","article-title":"Bilirubin in the liver-gut signaling axis","volume":"29","author":"Hamoud","year":"2018","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Kennedy, D.J., Khalaf, F.K., Sheehy, B., Weber, M.E., Agatisa-Boyle, B., Conic, J., Hauser, K., Medert, C.M., Westfall, K., and Bucur, P. (2018). Telocinobufagin, a novel cardiotonic steroid, promotes renal fibrosis via Na(+)\/K(+)-ATPase profibrotic signaling pathways. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19092566"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Khalaf, F.K., Dube, P., Mohamed, A., Tian, J., Malhotra, D., Haller, S.T., and Kennedy, D.J. (2018). Cardiotonic steroids and the sodium trade balance: New Insights into trade-off mechanisms mediated by the Na(+)\/K(+)-ATPase. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19092576"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1124\/pr.108.000711","article-title":"Endogenous cardiotonic steroids: Physiology, pharmacology, and novel therapeutic targets","volume":"61","author":"Bagrov","year":"2009","journal-title":"Pharmacol. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1161\/01.HYP.0000252409.36927.05","article-title":"Marinobufagenin stimulates fibroblast collagen production and causes fibrosis in experimental uremic cardiomyopathy","volume":"49","author":"Elkareh","year":"2007","journal-title":"Hypertension"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1161\/CIRCHEARTFAILURE.114.001976","article-title":"Elevated plasma marinobufagenin, an endogenous cardiotonic steroid, is associated with right ventricular dysfunction and nitrative stress in heart failure","volume":"8","author":"Kennedy","year":"2015","journal-title":"Circ. Heart Fail."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"F1219","DOI":"10.1152\/ajprenal.90710.2008","article-title":"Marinobufagenin induces increases in procollagen expression in a process involving protein kinase C and Fli-1: Implications for uremic cardiomyopathy","volume":"296","author":"Elkareh","year":"2009","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2912","DOI":"10.1093\/ndt\/gfq772","article-title":"Endogenous cardiotonic steroids in chronic renal failure","volume":"26","author":"Kolmakova","year":"2011","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"F922","DOI":"10.1152\/ajprenal.90605.2008","article-title":"The cardiotonic steroid hormone marinobufagenin induces renal fibrosis: Implication of epithelial-to-mesenchymal transition","volume":"296","author":"Fedorova","year":"2009","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"184","DOI":"10.4254\/wjh.v4.i6.184","article-title":"Regulation and deregulation of cholesterol homeostasis: The liver as a metabolic \u201cpower station\u201d","volume":"4","author":"Trapani","year":"2012","journal-title":"World J. Hepatol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1580","DOI":"10.1007\/s00018-009-9018-5","article-title":"Digoxin and ouabain increase the synthesis of cholesterol in human liver cells","volume":"66","author":"Campia","year":"2009","journal-title":"Cell Mol. Life Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1042\/BJ20120200","article-title":"Digoxin and ouabain induce the efflux of cholesterol via liver X receptor signalling and the synthesis of ATP in cardiomyocytes","volume":"447","author":"Campia","year":"2012","journal-title":"Biochem. J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"150","DOI":"10.3389\/fcell.2018.00150","article-title":"Role of Metabolism in hepatic stellate cell activation and fibrogenesis","volume":"6","author":"Hou","year":"2018","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1053\/j.gastro.2011.11.004","article-title":"Lipids in liver disease: Looking beyond steatosis","volume":"142","author":"Schwabe","year":"2012","journal-title":"Gastroenterology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1053\/j.gastro.2011.09.049","article-title":"A high-cholesterol diet exacerbates liver fibrosis in mice via accumulation of Free. cholesterol in hepatic stellate cells","volume":"142","author":"Teratani","year":"2012","journal-title":"Gastroenterology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.jhep.2014.03.018","article-title":"Acyl-CoA:cholesterol acyltransferase 1 mediates liver fibrosis by regulating Free. cholesterol accumulation in hepatic stellate cells","volume":"61","author":"Tomita","year":"2014","journal-title":"J. Hepatol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1111\/hepr.13040","article-title":"Vitamin A-coupled liposome system targeting Free. cholesterol accumulation in hepatic stellate cells offers a beneficial therapeutic strategy for liver fibrosis","volume":"48","author":"Furuhashi","year":"2018","journal-title":"Hepatol. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2548154","DOI":"10.1155\/2018\/2548154","article-title":"Hypoxic signaling and cholesterol lipotoxicity in fatty liver disease progression","volume":"2018","author":"Tirosh","year":"2018","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1765","DOI":"10.1016\/j.bbadis.2015.05.015","article-title":"Recent insights on the role of cholesterol in non-alcoholic fatty liver disease","volume":"1852","author":"Arguello","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s12950-019-0211-5","article-title":"Accumulation of Free. cholesterol and oxidized low-density lipoprotein is associated with portal inflammation and fibrosis in nonalcoholic fatty liver disease","volume":"16","author":"Ho","year":"2019","journal-title":"J. Inflamm."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1038\/labinvest.2015.67","article-title":"The role of iNOS in cholesterol-induced liver fibrosis","volume":"95","author":"Anavi","year":"2015","journal-title":"Lab. Investig."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Srikanthan, K., Shapiro, J.I., and Sodhi, K. (2016). The Role of Na\/K-ATPase signaling in oxidative stress related to obesity and cardiovascular disease. Molecules, 21.","DOI":"10.3390\/molecules21091172"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Pratt, R.D., Brickman, C.R., Cottrill, C.L., Shapiro, J.I., and Liu, J. (2018). The Na\/K-ATPase signaling: From specific ligands to general reactive oxygen species. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19092600"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.1016\/j.bbadis.2010.01.013","article-title":"The sodium pump and cardiotonic steroids-induced signal transduction protein kinases and calcium-signaling microdomain in regulation of transporter trafficking","volume":"1802","author":"Liu","year":"2010","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Bartlett, D.E., Miller, R.B., Thiesfeldt, S., Lakhani, H.V., Shapiro, J.I., and Sodhi, K. (2018). The Role of Na\/K-ATPase signaling in oxidative stress related to aging: Implications in obesity and cardiovascular disease. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19072139"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"21066","DOI":"10.1074\/jbc.M109.013821","article-title":"NaKtide, a Na\/K-ATPase-derived peptide Src inhibitor, antagonizes ouabain-activated signal transduction in cultured cells","volume":"284","author":"Li","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1038\/s41598-017-00306-5","article-title":"pNaKtide attenuates steatohepatitis and atherosclerosis by blocking Na\/K-ATPase\/ROS Amplification in C57Bl6 and apoe knockout mice fed. A western diet","volume":"7","author":"Sodhi","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"9721","DOI":"10.1038\/s41598-018-26768-9","article-title":"The Na\/K-ATPase oxidant amplification loop regulates aging","volume":"8","author":"Sodhi","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Zehra, M., Curry, J.C., Pillai, S.S., Lakhani, H.V., Edwards, C.E., and Sodhi, K. (2020). Elucidating potential profibrotic mechanisms of emerging biomarkers for early prognosis of hepatic fibrosis. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21134737"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e1500781","DOI":"10.1126\/sciadv.1500781","article-title":"pNaKtide inhibits Na\/K-ATPase reactive oxygen species amplification and attenuates adipogenesis","volume":"1","author":"Sodhi","year":"2015","journal-title":"Sci. Adv."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Dongiovanni, P., Meroni, M., Longo, M., Fargion, S., and Fracanzani, A.L. (2018). miRNA Signature in NAFLD: A turning point. For a non-invasive diagnosis. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19123966"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1038\/nrendo.2015.25","article-title":"MicroRNA regulatory networks in human adipose tissue and obesity","volume":"11","author":"Arner","year":"2015","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1055\/s-0034-1397345","article-title":"MicroRNAs in fatty liver disease","volume":"35","author":"Sobolewski","year":"2015","journal-title":"Semin. Liver Dis."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1314","DOI":"10.1007\/s10620-015-4002-4","article-title":"Role of MicroRNAs in NAFLD\/NASH","volume":"61","author":"Szabo","year":"2016","journal-title":"Dig. Dis. Sci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2096161","DOI":"10.1155\/2019\/2096161","article-title":"Circulating miRNAs as novel diagnostic biomarkers in nonalcoholic fatty liver disease: A Systematic review and meta-analysis","volume":"2019","author":"Cai","year":"2019","journal-title":"Can. J. Gastroenterol. Hepatol."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Cermelli, S., Ruggieri, A., Marrero, J.A., Ioannou, G.N., and Beretta, L. (2011). Circulating microRNAs in patients with chronic hepatitis C and non-alcoholic fatty liver disease. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0023937"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"800","DOI":"10.1136\/gutjnl-2014-306996","article-title":"Circulating microRNA signature in non-alcoholic fatty liver disease: From serum non-coding RNAs to liver histology and disease pathogenesis","volume":"64","author":"Pirola","year":"2015","journal-title":"Gut"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1977","DOI":"10.3390\/jcm4121953","article-title":"MicroRNAs in nonalcoholic fatty liver disease","volume":"4","author":"Baffy","year":"2015","journal-title":"J. Clin. Med."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1055\/s-0034-1397348","article-title":"Circulating microRNAs: Emerging biomarkers of liver disease","volume":"35","author":"Arrese","year":"2015","journal-title":"Semin. Liver Dis."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1002\/hep.29367","article-title":"The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American association for the study of liver diseases","volume":"67","author":"Chalasani","year":"2018","journal-title":"Hepatology"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Long, M.T., Gandhi, S., and Loomba, R. (2020). Advances in non-invasive biomarkers for the diagnosis and monitoring of non-alcoholic fatty liver disease. Metabolism, 154259.","DOI":"10.1016\/j.metabol.2020.154259"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4172\/2155-9899.1000393","article-title":"Role of serum biomarkers in early detection of non-alcoholic steatohepatitis and fibrosis in west Virginian children","volume":"7","author":"Sodhi","year":"2016","journal-title":"J. Clin. Cell Immunol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"10606","DOI":"10.1038\/s41598-018-28854-4","article-title":"Non-invasive prediction of NAFLD severity: A comprehensive, independent validation of previously postulated serum microRNA biomarkers","volume":"8","author":"Conde","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/j.jhep.2017.11.013","article-title":"Non-invasive assessment of non-alcoholic fatty liver disease: Clinical prediction rules and blood-based biomarkers","volume":"68","author":"Chalasani","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"e2630","DOI":"10.1097\/MD.0000000000002630","article-title":"Prediction of nonalcoholic fatty liver disease via a novel panel of serum adipokines","volume":"95","author":"Jamali","year":"2016","journal-title":"Medicine"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1002\/hep.28776","article-title":"Novel plasma biomarkers associated with liver disease severity in adults with nonalcoholic fatty liver disease","volume":"65","author":"Ajmera","year":"2017","journal-title":"Hepatology"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Yang, M., Xu, D., Liu, Y., Guo, X., Li, W., Guo, C., Zhang, H., Gao, Y., Mao, Y., and Zhao, J. (2015). Combined Serum Biomarkers in Non-Invasive Diagnosis of Non-Alcoholic Steatohepatitis. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0131664"},{"key":"ref_61","first-page":"783976","article-title":"Nonalcoholic Fatty liver disease: Focus on lipoprotein and lipid deregulation","volume":"2011","author":"Rozman","year":"2011","journal-title":"J. Lipids"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1111\/j.2040-1124.2011.00134.x","article-title":"Impact of glucose tolerance on the severity of non-alcoholic steatohepatitis","volume":"2","author":"Nakamura","year":"2011","journal-title":"J. Diabetes Investig."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"597","DOI":"10.4103\/2230-8210.163172","article-title":"Profile of liver enzymes in non-alcoholic fatty liver disease in patients with impaired glucose tolerance and newly detected untreated type 2 diabetes","volume":"19","author":"Sanyal","year":"2015","journal-title":"Indian J. Endocrinol. Metab."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1007\/s12020-020-02319-z","article-title":"Albumin binding function is a novel biomarker for early liver damage and disease progression in non-alcoholic fatty liver disease","volume":"69","author":"Sun","year":"2020","journal-title":"Endocrine"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"4649","DOI":"10.1038\/s41598-017-04631-7","article-title":"Liver fat, hepatic enzymes, alkaline phosphatase and the risk of incident type 2 diabetes: A prospective study of 132,377 adults","volume":"7","author":"Chen","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_66","first-page":"626","article-title":"Alkaline phosphatase: Can it be considered as an indicator of liver fibrosis in non-alcoholic steatohepatitis with type 2 diabetes?","volume":"112","author":"Kocabay","year":"2011","journal-title":"Bratisl. Lek Listy"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"5250","DOI":"10.2174\/13816128113199990344","article-title":"Pathophysiology of NASH: Perspectives for a targeted treatment","volume":"19","author":"Marra","year":"2013","journal-title":"Curr. Pharm. Des."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"476380","DOI":"10.1155\/2012\/476380","article-title":"Inflammation as a Link between obesity and metabolic syndrome","volume":"2012","author":"Emanuela","year":"2012","journal-title":"J. Nutr. Metab."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1591","DOI":"10.7150\/ijms.27953","article-title":"Phenotypic alteration of hepatocytes in non-alcoholic fatty liver disease","volume":"15","author":"Lakhani","year":"2018","journal-title":"Int. J. Med. Sci."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"327","DOI":"10.7555\/JBR.31.20160153","article-title":"Non-alcoholic fatty liver disease--a chronic disease of the 21st century","volume":"32","author":"Metrakos","year":"2018","journal-title":"J. Biomed. Res."},{"key":"ref_71","first-page":"3338","article-title":"Elevated levels of interleukin 6 are reduced in serum and subcutaneous adipose tissue of obese women after weight loss","volume":"85","author":"Bastard","year":"2000","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1172\/JCI25102","article-title":"Inflammation, stress, and diabetes","volume":"115","author":"Wellen","year":"2005","journal-title":"J. Clin. Investig."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1053\/jhep.2003.50316","article-title":"Cytokines and NASH: A pilot study of the effects of lifestyle modification and vitamin E","volume":"38","author":"Kugelmas","year":"2003","journal-title":"Hepatology"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"299","DOI":"10.2174\/156652409787847191","article-title":"Nonalcoholic fatty liver disease: The pathogenetic roles of insulin resistance and adipocytokines","volume":"9","author":"Polyzos","year":"2009","journal-title":"Curr. Mol. Med."},{"key":"ref_75","first-page":"2801","article-title":"Adiponectin, a key adipokine in obesity related liver diseases","volume":"17","author":"Buechler","year":"2011","journal-title":"World J. Gastroenterol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1515\/bc.2010.104","article-title":"Molecular mechanisms of signal transduction via adiponectin and adiponectin receptors","volume":"391","author":"Heiker","year":"2010","journal-title":"Biol. Chem."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2278","DOI":"10.1111\/j.1742-4658.2009.06955.x","article-title":"Full-length adiponectin protects hepatocytes from palmitate-induced apoptosis via inhibition of c-Jun NH2 terminal kinase","volume":"276","author":"Jung","year":"2009","journal-title":"FEBS J."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1006\/bbrc.1999.0255","article-title":"Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity","volume":"257","author":"Arita","year":"1999","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.metabol.2010.09.003","article-title":"Serum total adiponectin in nonalcoholic fatty liver disease: A systematic review and meta-analysis","volume":"60","author":"Polyzos","year":"2011","journal-title":"Metabolism"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"93","DOI":"10.7326\/0003-4819-152-2-201001190-00008","article-title":"Narrative review: The role of leptin in human physiology: Emerging clinical applications","volume":"152","author":"Kelesidis","year":"2010","journal-title":"Ann. Intern. Med."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1053\/jhep.2001.26518","article-title":"Leptin augments inflammatory and profibrogenic responses in the murine liver induced by hepatotoxic chemicals","volume":"34","author":"Ikejima","year":"2001","journal-title":"Hepatology"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1038\/nrd2589","article-title":"Fatty acid-binding proteins: Role in metabolic diseases and potential as drug targets","volume":"7","author":"Furuhashi","year":"2008","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Shi, J., Zhang, Y., Gu, W., Cui, B., Xu, M., Yan, Q., Wang, W., Ning, G., and Hong, J. (2012). Serum liver fatty acid binding protein levels correlate positively with obesity and insulin resistance in Chinese young adults. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0048777"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"182","DOI":"10.7150\/ijms.40417","article-title":"Circulating fatty acid-binding protein 1 (FABP1) and nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus","volume":"17","author":"Lu","year":"2020","journal-title":"Int. J. Med. Sci."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"2661","DOI":"10.3748\/wjg.v24.i25.2661","article-title":"Apoptosis and non-alcoholic fatty liver diseases","volume":"24","author":"Kanda","year":"2018","journal-title":"World J. Gastroenterol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1002\/hep.21223","article-title":"In vivo assessment of liver cell apoptosis as a novel biomarker of disease severity in nonalcoholic fatty liver disease","volume":"44","author":"Wieckowska","year":"2006","journal-title":"Hepatology"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1002\/hep.23050","article-title":"Cytokeratin-18 fragment levels as noninvasive biomarkers for nonalcoholic steatohepatitis: A multicenter validation study","volume":"50","author":"Feldstein","year":"2009","journal-title":"Hepatology"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.cmet.2006.01.005","article-title":"miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting","volume":"3","author":"Esau","year":"2006","journal-title":"Cell Metab."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1530\/EJE-14-0867","article-title":"Elevated circulating microRNA-122 is associated with obesity and insulin resistance in young adults","volume":"172","author":"Wang","year":"2015","journal-title":"Eur. J. Endocrinol."},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Auguet, T., Aragones, G., Berlanga, A., Guiu-Jurado, E., Marti, A., Martinez, S., Sabench, F., Hernandez, M., Aguilar, C., and Sirvent, J.J. (2016). miR33a\/miR33b* and miR122 as possible contributors to hepatic lipid metabolism in obese women with nonalcoholic fatty liver disease. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17101620"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.cca.2013.05.021","article-title":"Associations between circulating microRNAs (miR-21, miR-34a, miR-122 and miR-451) and non-alcoholic fatty liver","volume":"424","author":"Yamada","year":"2013","journal-title":"Clin. Chim. Acta"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1615\/CritRevEukaryotGeneExpr.2015015396","article-title":"MicroRNA-34 Family and Its Role in Cardiovascular Disease","volume":"25","author":"Li","year":"2015","journal-title":"Crit. Rev. Eukaryot. Gene Expr."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1938","DOI":"10.3390\/jcm4111938","article-title":"MicroRNA Expression Relating to Dietary-Induced Liver Steatosis and NASH","volume":"4","author":"Zarfeshani","year":"2015","journal-title":"J. Clin. Med."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"13729","DOI":"10.1038\/srep13729","article-title":"Effect of miR-34a in regulating steatosis by targeting PPARalpha expression in nonalcoholic fatty liver disease","volume":"5","author":"Ding","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"16137","DOI":"10.1073\/pnas.1205951109","article-title":"Aberrantly elevated microRNA-34a in obesity attenuates hepatic responses to FGF19 by targeting a membrane coreceptor beta-Klotho","volume":"109","author":"Fu","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"25776","DOI":"10.1074\/jbc.M116.752311","article-title":"Glucocorticoid receptor beta induces hepatic steatosis by augmenting inflammation and inhibition of the peroxisome proliferator-activated receptor (PPAR) alpha","volume":"291","author":"Marino","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_97","first-page":"5589","article-title":"miR-34a and miR-125b are upregulated in peripheral blood mononuclear cells from patients with type 2 diabetes mellitus","volume":"14","author":"Shen","year":"2017","journal-title":"Exp. Ther. Med."},{"key":"ref_98","first-page":"149","article-title":"The association of plasma levels of miR-34a AND miR-149 with obesity and insulin resistance in obese children and adolescents","volume":"14","author":"Ahmadpour","year":"2018","journal-title":"Acta Endocrinol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"9844","DOI":"10.3748\/wjg.v22.i44.9844","article-title":"Disease-specific miR-34a as diagnostic marker of non-alcoholic steatohepatitis in a Chinese population","volume":"22","author":"Liu","year":"2016","journal-title":"World J. Gastroenterol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"5813","DOI":"10.1073\/pnas.0810550106","article-title":"miR-375 maintains normal pancreatic alpha- and beta-cell mass","volume":"106","author":"Poy","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"484696","DOI":"10.1155\/2012\/484696","article-title":"MicroRNAs in insulin resistance and obesity","volume":"2012","author":"Williams","year":"2012","journal-title":"Exp. Diabetes Res."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/j.jhep.2017.10.011","article-title":"Galpha12 overexpression induced by miR-16 dysregulation contributes to liver fibrosis by promoting autophagy in hepatic stellate cells","volume":"68","author":"Kim","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1053\/j.gastro.2011.12.044","article-title":"Autophagy releases lipid that promotes fibrogenesis by activated hepatic stellate cells in mice and in human tissues","volume":"142","author":"Rozenfeld","year":"2012","journal-title":"Gastroenterology"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"2043","DOI":"10.1007\/s00705-015-2474-3","article-title":"Increased miR-16 expression induced by hepatitis C virus infection promotes liver fibrosis through downregulation of hepatocyte growth factor and Smad7","volume":"160","author":"Zhu","year":"2015","journal-title":"Arch. Virol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1850","DOI":"10.1136\/gutjnl-2014-308430","article-title":"MicroRNA-21 is a potential link between non-alcoholic fatty liver disease and hepatocellular carcinoma via modulation of the HBP1-p53-Srebp1c pathway","volume":"65","author":"Wu","year":"2016","journal-title":"Gut"},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Zhao, J., Tang, N., Wu, K., Dai, W., Ye, C., Shi, J., Zhang, J., Ning, B., Zeng, X., and Lin, Y. (2014). MiR-21 simultaneously regulates ERK1 signaling in HSC activation and hepatocyte EMT in hepatic fibrosis. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0108005"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1038\/s41440-017-0009-x","article-title":"Marinobufagenin is related to elevated central and 24-h systolic blood pressures in young black women: The African-PREDICT Study","volume":"41","author":"Strauss","year":"2018","journal-title":"Hypertens. Res."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"290","DOI":"10.2337\/dc19-1071","article-title":"Performance of plasma biomarkers and diagnostic panels for nonalcoholic steatohepatitis and advanced fibrosis in patients with type 2 diabetes","volume":"43","author":"Bril","year":"2020","journal-title":"Diabetes Care"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"543","DOI":"10.7150\/ijms.18988","article-title":"Existence of a strong correlation of biomarkers and miRNA in females with metabolic syndrome and obesity in a population of west Virginia","volume":"14","author":"Klug","year":"2017","journal-title":"Int. J. Med. Sci."},{"key":"ref_110","doi-asserted-by":"crossref","unstructured":"Lakhani, H.V., Khanal, T., Gabi, A., Yousef, G., Alam, M.B., Sharma, D., Aljoudi, H., Puri, N., Thompson, E., and Shapiro, J.I. (2018). Developing a panel of biomarkers and miRNA in patients with myocardial infarction for early intervention strategies of heart failure in West Virginian population. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0205329"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/18\/6698\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:09:33Z","timestamp":1760177373000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/18\/6698"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,9,13]]},"references-count":110,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2020,9]]}},"alternative-id":["ijms21186698"],"URL":"https:\/\/doi.org\/10.3390\/ijms21186698","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,9,13]]}}}