{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T13:22:12Z","timestamp":1790256132695,"version":"4.1.0"},"reference-count":75,"publisher":"Walter de Gruyter GmbH","issue":"4","license":[{"start":{"date-parts":[[2019,12,1]],"date-time":"2019-12-01T00:00:00Z","timestamp":1575158400000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/3.0"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Non-alcoholic fatty liver disease (NAFLD) is closely associated with metabolic diseases like type 2 diabetes and obesity. In recent decades, accumulating evidence has revealed that the hepatokines, proteins mainly secreted by the liver, play important roles in the development of NAFLD by acting directly on the lipid and glucose metabolism. As a member of organokines, the hepatokines establish the communication between the liver and the adipose, muscular tissues. In this review, we summarize the current understanding of the hepatokines and how they modulate the pathogenesis of metabolic disorders especially NAFLD.<\/jats:p>","DOI":"10.2478\/jtim-2019-0029","type":"journal-article","created":{"date-parts":[[2020,1,18]],"date-time":"2020-01-18T09:31:06Z","timestamp":1579339866000},"page":"143-148","source":"Crossref","is-referenced-by-count":44,"title":["Role of hepatokines in non-alcoholic fatty liver disease"],"prefix":"10.2478","volume":"7","author":[{"given":"Yini","family":"Ke","sequence":"first","affiliation":[{"name":"Department of Rheumatology and Immunology, the First Affiliated Hospital, College of Medicine , Zhejiang University , Hangzhou 310003 , Zhejiang Province, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengfu","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, the First Affiliated Hospital, College of Medicine , Zhejiang University , Hangzhou 310003 , Zhejiang Province, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, the First Affiliated Hospital, College of Medicine , Zhejiang University , Hangzhou 310003 , Zhejiang Province, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youming","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, the First Affiliated Hospital, College of Medicine , Zhejiang University , Hangzhou 310003 , Zhejiang Province, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"374","published-online":{"date-parts":[[2019,12,31]]},"reference":[{"key":"2023042508114209010_j_jtim-2019-0029_ref_001_w2aab3b7b5b1b6b1ab1b8b1Aa","doi-asserted-by":"crossref","unstructured":"Lee HW, Wong VW. Changing NAFLD Epidemiology in China. Hepatology 2019;70:1095\u20138.","DOI":"10.1002\/hep.30848"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_002_w2aab3b7b5b1b6b1ab1b8b2Aa","doi-asserted-by":"crossref","unstructured":"Younossi ZM, Golabi P, de Avila L, Minhui Paik J, Srishord M, Fukui N, et al. The Global Epidemiology of NAFLD and NASH in Patients with type 2 diabetes: A Systematic Review and Meta-analysis. J Hepatol 2019; 71:793\u2013801","DOI":"10.1016\/j.jhep.2019.06.021"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_003_w2aab3b7b5b1b6b1ab1b8b3Aa","doi-asserted-by":"crossref","unstructured":"Rinella ME. Nonalcoholic fatty liver disease: a systematic review. JAMA 2015;313:2263\u201373.","DOI":"10.1001\/jama.2015.5370"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_004_w2aab3b7b5b1b6b1ab1b8b4Aa","doi-asserted-by":"crossref","unstructured":"Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005;41:1313\u201321.","DOI":"10.1002\/hep.20701"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_005_w2aab3b7b5b1b6b1ab1b8b5Aa","doi-asserted-by":"crossref","unstructured":"Giorda C, Forlani G, Manti R, Mazzella N, De Cosmo S, Rossi MC, et al. Occurrence over time and regression of nonalcholic fatty liver disease in type 2 diabetes. Diabetes Metab Res Rev 2017;33.","DOI":"10.1002\/dmrr.2878"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_006_w2aab3b7b5b1b6b1ab1b8b6Aa","unstructured":"Federico A, Dallio M, Masarone M, Persico M, Loguercio C. The epidemiology of non-alcoholic fatty liver disease and its connection with cardiovascular disease: role of endothelial dysfunction. Eur Rev Med Pharmacol Sci 2016;20:4731\u201341."},{"key":"2023042508114209010_j_jtim-2019-0029_ref_007_w2aab3b7b5b1b6b1ab1b8b7Aa","doi-asserted-by":"crossref","unstructured":"Lebensztejn DM, Flisiak-Jackiewicz M, Bialokoz-Kalinowska I, Bobrus-Chociej A, Kowalska I. Hepatokines and non-alcoholic fatty liver disease. Acta Biochim Pol 2016;63:459\u201367.","DOI":"10.18388\/abp.2016_1252"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_008_w2aab3b7b5b1b6b1ab1b8b8Aa","doi-asserted-by":"crossref","unstructured":"Watt MJ, Miotto PM, De Nardo W, Montgomery MK. The liver as an endocrine organ - linking NAFLD and insulin resistance. Endocr Rev 2019;40:1367\u201393.","DOI":"10.1210\/er.2019-00034"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_009_w2aab3b7b5b1b6b1ab1b8b9Aa","doi-asserted-by":"crossref","unstructured":"Hotamisligil GS. Inflammation and metabolic disorders. Nature 2006;444:860\u20137.","DOI":"10.1038\/nature05485"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_010_w2aab3b7b5b1b6b1ab1b8c10Aa","doi-asserted-by":"crossref","unstructured":"Chatterjee P, Seal S, Mukherjee S, Kundu R, Mukherjee S, Ray S, et al. Adipocyte fetuin-A contributes to macrophage migration into adipose tissue and polarization of macrophages. J Biol Chem 2013;288:28324\u201330.","DOI":"10.1074\/jbc.C113.495473"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_011_w2aab3b7b5b1b6b1ab1b8c11Aa","doi-asserted-by":"crossref","unstructured":"Denecke B, Graber S, Schafer C, Heiss A, Woltje M, Jahnen-Dechent W. Tissue distribution and activity testing suggest a similar but not identical function of fetuin-B and fetuin-A. Biochem J 2003;376:135\u201345.","DOI":"10.1042\/bj20030676"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_012_w2aab3b7b5b1b6b1ab1b8c12Aa","doi-asserted-by":"crossref","unstructured":"Mori K, Emoto M, Yokoyama H, Araki T, Teramura M, Koyama H, et al. Association of serum fetuin-A with insulin resistance in type 2 diabetic and nondiabetic subjects. Diabetes Care 2006;29:468.","DOI":"10.2337\/diacare.29.02.06.dc05-1484"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_013_w2aab3b7b5b1b6b1ab1b8c13Aa","doi-asserted-by":"crossref","unstructured":"Mathews ST, Singh GP, Ranalletta M, Cintron VJ, Qiang XL, Goustin AS, et al. Improved insulin sensitivity and resistance to weight gain in mice null for the Ahsg gene. Diabetes 2002;51:2450\u20138.","DOI":"10.2337\/diabetes.51.8.2450"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_014_w2aab3b7b5b1b6b1ab1b8c14Aa","doi-asserted-by":"crossref","unstructured":"Andersen G, Burgdorf KS, Sparso T, Borch-Johnsen K, Jorgensen T, Hansen T, et al. AHSG tag single nucleotide Polymorphisms associate with type 2 diabetes and dyslipidemia: Studies of metabolic traits in 7,683 white danish subjects. Diabetes 2008;57:1427\u201332.","DOI":"10.2337\/db07-0558"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_015_w2aab3b7b5b1b6b1ab1b8c15Aa","doi-asserted-by":"crossref","unstructured":"Stefan N, Hennige AM, Staiger H, Machann J, Schick F, Krober SM, et al. Alpha(2)-Heremans-Schmid glycoprotein\/fetuin-A is associated with insulin resistance and fat accumulation in the liver in humans. Diabetes Care 2006;29:853\u20137.","DOI":"10.2337\/diacare.29.04.06.dc05-1938"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_016_w2aab3b7b5b1b6b1ab1b8c16Aa","doi-asserted-by":"crossref","unstructured":"Reinehr T, Roth CL. Fetuin-A and Its Relation to Metabolic Syndrome and Fatty Liver Disease in Obese Children Before and After Weight Loss. J Clin Endocrinol Metab 2008;93:4479\u201385.","DOI":"10.1210\/jc.2008-1505"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_017_w2aab3b7b5b1b6b1ab1b8c17Aa","doi-asserted-by":"crossref","unstructured":"Dogru T, Genc H, Tapan S, Aslan F, Ercin CN, Ors F, et al. Plasma fetuin-A is associated with endothelial dysfunction and subclinical atherosclerosis in subjects with nonalcoholic fatty liver disease. Clin Endocrinol (Oxf) 2013;78:712\u20137.","DOI":"10.1111\/j.1365-2265.2012.04460.x"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_018_w2aab3b7b5b1b6b1ab1b8c18Aa","doi-asserted-by":"crossref","unstructured":"Perez-Sotelo D, Roca-Rivada A, Larrosa-Garcia M, Castelao C, Baamonde I, Baltar J, et al. Visceral and subcutaneous adipose tissue express and secrete functional alpha2hsglycoprotein (fetuin a) especially in obesity. Endocrine 2017;55:435\u201346.","DOI":"10.1007\/s12020-016-1132-1"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_019_w2aab3b7b5b1b6b1ab1b8c19Aa","doi-asserted-by":"crossref","unstructured":"Takata H, Ikeda Y, Suehiro T, Ishibashi A, Inoue M, Kumon Y, et al. High Glucose Induces Transactivation of the alpha 2-HS Glycoprotein Gene Through the ERK1\/2 Signaling Pathway. J Atheroscler Thromb 2009;16:448\u201356.","DOI":"10.5551\/jat.No950"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_020_w2aab3b7b5b1b6b1ab1b8c20Aa","doi-asserted-by":"crossref","unstructured":"Lee KY, Lee W, Jung SH, Park J, Sim H, Choi YJ, et al. Hepatic upregulation of fetuin-A mediates acetaminophen-induced liver injury through activation of TLR4 in mice. Biochem Pharmacol 2019;166:46\u201355.","DOI":"10.1016\/j.bcp.2019.05.011"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_021_w2aab3b7b5b1b6b1ab1b8c21Aa","doi-asserted-by":"crossref","unstructured":"Pal D, Dasgupta S, Kundu R, Maitra S, Das G, Mukhopadhyay S, et al. Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance. Nat Med 2012;18:1279\u201385.","DOI":"10.1038\/nm.2851"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_022_w2aab3b7b5b1b6b1ab1b8c22Aa","doi-asserted-by":"crossref","unstructured":"Hennige AM, Staiger H, Wicke C, Machicao F, Fritsche A, Haering HU, et al. Fetuin-A Induces Cytokine Expression and Suppresses Adiponectin Production. PLoS One 2008;3: e1765.","DOI":"10.1371\/journal.pone.0001765"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_023_w2aab3b7b5b1b6b1ab1b8c23Aa","doi-asserted-by":"crossref","unstructured":"Heinrichsdorff J, Olefsky JM. Fetuin-A: the missing link in lipid-induced inflammation. Nat Med 2012;18:1182\u20133.","DOI":"10.1038\/nm.2869"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_024_w2aab3b7b5b1b6b1ab1b8c24Aa","doi-asserted-by":"crossref","unstructured":"Nishimura T, Nakatake Y, Konishi M, Itoh N. Identification of a novel FGF, FGF-21, preferentially expressed in the liver. Biochim Biophys Acta 2000;1492:203\u20136.","DOI":"10.1016\/S0167-4781(00)00067-1"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_025_w2aab3b7b5b1b6b1ab1b8c25Aa","doi-asserted-by":"crossref","unstructured":"Fon Tacer K, Bookout AL, Ding X, Kurosu H, John GB, Wang L, et al. Research resource: Comprehensive expression atlas of the fibroblast growth factor system in adult mouse. Mol Endocrinol 2010;24:2050\u201364.","DOI":"10.1210\/me.2010-0142"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_026_w2aab3b7b5b1b6b1ab1b8c26Aa","doi-asserted-by":"crossref","unstructured":"Yilmaz Y, Eren F, Yonal O, Kurt R, Aktas B, Celikel CA, et al. Increased serum FGF21 levels in patients with nonalcoholic fatty liver disease. Eur J Clin Invest 2010;40:887\u201392.","DOI":"10.1111\/j.1365-2362.2010.02338.x"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_027_w2aab3b7b5b1b6b1ab1b8c27Aa","doi-asserted-by":"crossref","unstructured":"Yang C, Lu W, Lin T, You P, Ye M, Huang Y, et al. Activation of Liver FGF21 in hepatocarcinogenesis and during hepatic stress. BMC Gastroenterol 2013;13:67.","DOI":"10.1186\/1471-230X-13-67"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_028_w2aab3b7b5b1b6b1ab1b8c28Aa","doi-asserted-by":"crossref","unstructured":"Keuper M, Haring H-U, Staiger H. Circulating FGF21 Levels in Human Health and Metabolic Disease. Exp Clin Endocrinol Diabetes 2019.","DOI":"10.1055\/a-0879-2968"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_029_w2aab3b7b5b1b6b1ab1b8c29Aa","doi-asserted-by":"crossref","unstructured":"Fisher FM, Chui PC, Nasser IA, Popov Y, Cunniff JC, Lundasen T, et al. Fibroblast Growth Factor 21 Limits Lipotoxicity by Promoting Hepatic Fatty Acid Activation in Mice on Methionine and Choline-Deficient Diets. Gastroenterology 2014;147:1073\u201383.","DOI":"10.1053\/j.gastro.2014.07.044"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_030_w2aab3b7b5b1b6b1ab1b8c30Aa","doi-asserted-by":"crossref","unstructured":"Kim SH, Kim KH, Kim H-K, Kim M-J, Back SH, Konishi M, et al. Fibroblast growth factor 21 participates in adaptation to endoplasmic reticulum stress and attenuates obesity-induced hepatic metabolic stress. Diabetologia 2015;58:809\u201318.","DOI":"10.1007\/s00125-014-3475-6"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_031_w2aab3b7b5b1b6b1ab1b8c31Aa","doi-asserted-by":"crossref","unstructured":"Jiang S, Zhang R, Li H, Fang Q, Jiang F, Hou X, et al. The Single Nucleotide Polymorphism rs499765 Is Associated with Fibroblast Growth Factor 21 and Nonalcoholic Fatty Liver Disease in a Chinese Population with Normal Glucose Tolerance. J Nutrigenet Nutrigenomics 2014;7:121\u20139.","DOI":"10.1159\/000367943"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_032_w2aab3b7b5b1b6b1ab1b8c32Aa","doi-asserted-by":"crossref","unstructured":"Reinehr T, Woelfle J, Wunsch R, Roth CL. Fibroblast Growth Factor 21 (FGF-21) and Its Relation to Obesity, Metabolic Syndrome, and Nonalcoholic Fatty Liver in Children: A Longitudinal Analysis. J Clin Endocrinol Metab 2012;97:2143\u201350.","DOI":"10.1210\/jc.2012-1221"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_033_w2aab3b7b5b1b6b1ab1b8c33Aa","doi-asserted-by":"crossref","unstructured":"Dushay J, Chui PC, Gopalakrishnan GS, Varela-Rey M, Crawley M, Fisher FM, et al. Increased Fibroblast Growth Factor 21 in Obesity and Nonalcoholic Fatty Liver Disease. Gastroenterology 2010;139:456\u201363.","DOI":"10.1053\/j.gastro.2010.04.054"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_034_w2aab3b7b5b1b6b1ab1b8c34Aa","doi-asserted-by":"crossref","unstructured":"Li H, Fang Q, Gao F, Fan J, Zhou J, Wang X, et al. Fibroblast growth factor 21 levels are increased in nonalcoholic fatty liver disease patients and are correlated with hepatic triglyceride. J Hepatol 2010;53:934\u201340.","DOI":"10.1016\/j.jhep.2010.05.018"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_035_w2aab3b7b5b1b6b1ab1b8c35Aa","doi-asserted-by":"crossref","unstructured":"Giannini C, Feldstein AE, Santoro N, Kim G, Kursawe R, Pierpont B, et al. Circulating Levels of FGF-21 in Obese Youth: Associations With Liver Fat Content and Markers of Liver Damage. J Clin Endocrinol Metab 2013;98:2993\u20133000.","DOI":"10.1210\/jc.2013-1250"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_036_w2aab3b7b5b1b6b1ab1b8c36Aa","doi-asserted-by":"crossref","unstructured":"Tanaka N, Takahashi S, Zhang Y, Krausz KW, Smith PB, Patterson AD, et al. Role of fibroblast growth factor 21 in the early stage of NASH induced by methionine- and choline-deficient diet. Biochim Biophys Acta 2015;1852:1242\u201352.","DOI":"10.1016\/j.bbadis.2015.02.012"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_037_w2aab3b7b5b1b6b1ab1b8c37Aa","doi-asserted-by":"crossref","unstructured":"Chartoumpekis DV, Ziros PG, Psyrogiannis AI, Papavassiliou AG, Kyriazopoulou VE, Sykiotis GP, et al. Nrf2 Represses FGF21 During Long-Term High-Fat Diet-Induced Obesity in Mice. Diabetes 2011;60:2465\u201373.","DOI":"10.2337\/db11-0112"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_038_w2aab3b7b5b1b6b1ab1b8c38Aa","doi-asserted-by":"crossref","unstructured":"Diaz-Delfin J, Hondares E, Iglesias R, Giralt M, Caelles C, Villarroya F. TNF-alpha Represses beta-Klotho Expression and Impairs FGF21 Action in Adipose Cells: Involvement of JNK1 in the FGF21 Pathway. Endocrinology 2012;153:4238\u201345.","DOI":"10.1210\/en.2012-1193"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_039_w2aab3b7b5b1b6b1ab1b8c39Aa","doi-asserted-by":"crossref","unstructured":"Hui E, Xu A, Yang HB, Lam KSL. Obesity as the common soil of non-alcoholic fatty liver disease and diabetes: Role of adipokines. J Diabetes Investig 2013;4:413\u201325.","DOI":"10.1111\/jdi.12093"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_040_w2aab3b7b5b1b6b1ab1b8c40Aa","doi-asserted-by":"crossref","unstructured":"Badman MK, Pissios P, Kennedy AR, Koukos G, Flier JS, Maratos-Flier E. Hepatic fibroblast growth factor 21 is regulated by PPAR alpha and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab 2007;5:426\u201337.","DOI":"10.1016\/j.cmet.2007.05.002"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_041_w2aab3b7b5b1b6b1ab1b8c41Aa","doi-asserted-by":"crossref","unstructured":"Xu J, Lloyd DJ, Hale C, Stanislaus S, Chen M, Sivits G, et al. Fibroblast Growth Factor 21 Reverses Hepatic Steatosis, Increases Energy Expenditure, and Improves Insulin Sensitivity in Diet-Induced Obese Mice. Diabetes 2009;58:250\u20139.","DOI":"10.2337\/db08-0392"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_042_w2aab3b7b5b1b6b1ab1b8c42Aa","doi-asserted-by":"crossref","unstructured":"Zhang Y, Lei T, Huang JF, Wang SB, Zhou LL, Yang ZQ, et al. The link between fibroblast growth factor 21 and sterol regulatory element binding protein 1c during lipogenesis in hepatocytes. Mol Cell Endocrinol 2011;342:41\u20137.","DOI":"10.1016\/j.mce.2011.05.003"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_043_w2aab3b7b5b1b6b1ab1b8c43Aa","doi-asserted-by":"crossref","unstructured":"Coskun T, Bina HA, Schneider MA, Dunbar JD, Hu CC, Chen Y, et al. Fibroblast Growth Factor 21 Corrects Obesity in Mice. Endocrinology 2008;149:6018\u201327.","DOI":"10.1210\/en.2008-0816"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_044_w2aab3b7b5b1b6b1ab1b8c44Aa","doi-asserted-by":"crossref","unstructured":"Badman MK, Koester A, Flier JS, Kharitonenkov A, Maratos-Flier E. Fibroblast growth factor 21-deficient mice demonstrate impaired adaptation to ketosis. Endocrinology 2009;150:4931\u201340.","DOI":"10.1210\/en.2009-0532"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_045_w2aab3b7b5b1b6b1ab1b8c45Aa","doi-asserted-by":"crossref","unstructured":"Fletcher JA, Meers GM, Laughlin MH, Ibdah JA, Thyfault JP, Rector RS. Modulating fibroblast growth factor 21 in hyperphagic OLETF rats with daily exercise and caloric restriction. Appl Physiol Nutr Metab 2012;37:1054\u201362.","DOI":"10.1139\/h2012-091"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_046_w2aab3b7b5b1b6b1ab1b8c46Aa","doi-asserted-by":"crossref","unstructured":"Kharitonenkov A, Beals JM, Micanovic R, Strifler BA, Rathnachalam R, Wroblewski VJ, et al. Rational Design of a Fibroblast Growth Factor 21-Based Clinical Candidate, LY2405319. PLoS One 2013;8: e58575.","DOI":"10.1371\/journal.pone.0058575"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_047_w2aab3b7b5b1b6b1ab1b8c47Aa","doi-asserted-by":"crossref","unstructured":"Gaich G, Chien JY, Fu H, Glass LC, Deeg MA, Holland WL, et al. The Effects of LY2405319, an FGF21 Analog, in Obese Human Subjects with Type 2 Diabetes. Cell Metab 2013;18:333\u201340.","DOI":"10.1016\/j.cmet.2013.08.005"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_048_w2aab3b7b5b1b6b1ab1b8c48Aa","doi-asserted-by":"crossref","unstructured":"Hill KE, Dasouki M, Phillips JA 3rd, Burk RF. Human selenoprotein P gene maps to 5q31. Genomics 1996;36:550\u20131.","DOI":"10.1006\/geno.1996.0505"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_049_w2aab3b7b5b1b6b1ab1b8c49Aa","doi-asserted-by":"crossref","unstructured":"Gladyshev VN, Arner ES, Berry MJ, Brigelius-Flohe R, Bruford EA, Burk RF, et al. Selenoprotein Gene Nomenclature. J Biol Chem 2016;291:24036\u201340.","DOI":"10.1074\/jbc.M116.756155"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_050_w2aab3b7b5b1b6b1ab1b8c50Aa","doi-asserted-by":"crossref","unstructured":"Carlson BA, Novoselov SV, Kumaraswamy E, Lee BJ, Anver MR, Gladyshev VN, et al. Specific excision of the selenocysteine tRNA[Ser]Sec (Trsp) gene in mouse liver demonstrates an essential role of selenoproteins in liver function. J Biol Chem 2004;279:8011\u20137.","DOI":"10.1074\/jbc.M310470200"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_051_w2aab3b7b5b1b6b1ab1b8c51Aa","doi-asserted-by":"crossref","unstructured":"Hill KE, Zhou JD, McMahan WJ, Motley AK, Atkins JF, Gesteland RF, et al. Deletion of selenoprotein P alters distribution of selenium in the mouse. J Biol Chem 2003;278:13640\u20136.","DOI":"10.1074\/jbc.M300755200"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_052_w2aab3b7b5b1b6b1ab1b8c52Aa","doi-asserted-by":"crossref","unstructured":"Misu H, Takamura T, Takayama H, Hayashi H, Matsuzawa-Nagata N, Kurita S, et al. A liver-derived secretory protein, selenoprotein P, causes insulin resistance. Cell Metab 2010;12:483\u201395.","DOI":"10.1016\/j.cmet.2010.09.015"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_053_w2aab3b7b5b1b6b1ab1b8c53Aa","doi-asserted-by":"crossref","unstructured":"Yang SJ, Hwang SY, Choi HY, Yoo HJ, Seo JA, Kim SG, et al. Serum Selenoprotein P Levels in Patients with Type 2 Diabetes and Prediabetes: Implications for Insulin Resistance, Inflammation, and Atherosclerosis. J Clin Endocrinol Metab 2011;96:E1325\u20139.","DOI":"10.1210\/jc.2011-0620"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_054_w2aab3b7b5b1b6b1ab1b8c54Aa","doi-asserted-by":"crossref","unstructured":"Misu H, Takayama H, Saito Y, Mita Y, Kikuchi A, Ishii KA, et al. Deficiency of the hepatokine selenoprotein P increases responsiveness to exercise in mice through upregulation of reactive oxygen species and AMP-activated protein kinase in muscle. Nat Med 2017; 23:508\u201316.","DOI":"10.1038\/nm.4295"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_055_w2aab3b7b5b1b6b1ab1b8c55Aa","doi-asserted-by":"crossref","unstructured":"Khan MS, Knowles BB, Aden DP, Rosner W. Secretion of Testosterone-Estradiol-Binding Globulin by a Human Hepatoma-Derived Cell-Line. J Clin Endocrinol Metab 1981;53:448\u20139.","DOI":"10.1210\/jcem-53-2-448"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_056_w2aab3b7b5b1b6b1ab1b8c56Aa","doi-asserted-by":"crossref","unstructured":"Berube D, Seralini GE, Gagne R, Hammond GL. Localization of the Human Sex Hormone-Binding Globulin Gene (Shbg) to the Short Arm of Chromosome-17 (17p12\u2013p13). Cytogenet Cell Genet 1990;54:65\u20137.","DOI":"10.1159\/000132958"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_057_w2aab3b7b5b1b6b1ab1b8c57Aa","doi-asserted-by":"crossref","unstructured":"Perry JRB, Weedon MN, Langenberg C, Jackson AU, Lyssenko V, Sparso T, et al. Genetic evidence that raised sex hormone binding globulin (SHBG) levels reduce the risk of type 2 diabetes. Hum Mol Genet 2010;19:535\u201344.","DOI":"10.1093\/hmg\/ddp522"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_058_w2aab3b7b5b1b6b1ab1b8c58Aa","doi-asserted-by":"crossref","unstructured":"Lazo M, Zeb I, Nasir K, Tracy RP, Budoff MJ, Ouyang P, et al. Association Between Endogenous Sex Hormones and Liver Fat in a Multiethnic Study of Atherosclerosis. Clin Gastroenterol Hepatol 2015;13:1686\u201393.","DOI":"10.1016\/j.cgh.2014.12.033"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_059_w2aab3b7b5b1b6b1ab1b8c59Aa","doi-asserted-by":"crossref","unstructured":"Luo J, Chen Q, Shen T, Wang X, Fang W, Wu X, et al. Association of sex hormone-binding globulin with nonalcoholic fatty liver disease in Chinese adults. Nutr Metab (Lond) 2018;15:79.","DOI":"10.1186\/s12986-018-0313-8"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_060_w2aab3b7b5b1b6b1ab1b8c60Aa","doi-asserted-by":"crossref","unstructured":"Hua X, Li M, Pan F, Xiao Y, Cui W, Hu Y. Non-alcoholic fatty liver disease is an influencing factor for the association of SHBG with metabolic syndrome in diabetes patients. Sci Rep 2017;7:14532.","DOI":"10.1038\/s41598-017-15232-9"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_061_w2aab3b7b5b1b6b1ab1b8c61Aa","doi-asserted-by":"crossref","unstructured":"Polyzos SA, Kountouras J, Tsatsoulis A, Zafeiriadou E, Katsiki E, Patsiaoura K, et al. Sex steroids and sex hormone-binding globulin in postmenopausal women with nonalcoholic fatty liver disease. Hormones (Athens) 2013;12:405\u201316.","DOI":"10.1007\/BF03401306"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_062_w2aab3b7b5b1b6b1ab1b8c62Aa","doi-asserted-by":"crossref","unstructured":"Hua X, Sun Y, Zhong Y, Feng W, Huang H, Wang W, et al. Low serum sex hormone-binding globulin is associated with nonalcoholic fatty liver disease in type 2 diabetic patients. Clin Endocrinol (Oxf) 2014;80:877\u201383.","DOI":"10.1111\/cen.12360"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_063_w2aab3b7b5b1b6b1ab1b8c63Aa","doi-asserted-by":"crossref","unstructured":"Stefan N, Schick F, Haering HU. Sex Hormone-Binding Globulin and Risk of Type 2 Diabetes. N Engl J Med 2009;361:2675\u20136.","DOI":"10.1056\/NEJMc0910143"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_064_w2aab3b7b5b1b6b1ab1b8c64Aa","doi-asserted-by":"crossref","unstructured":"Kavanagh K, Espeland MA, Sutton-Tyrrell K, Barinas-Mitchell E, El Khoudary SR, Wildman RP. Liver Fat and SHBG Affect Insulin Resistance in Midlife Women: The Study of Women\u2019s Health Across the Nation (SWAN). Obesity (Silver Spring) 2013;21:1031\u20138.","DOI":"10.1002\/oby.20077"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_065_w2aab3b7b5b1b6b1ab1b8c65Aa","doi-asserted-by":"crossref","unstructured":"Simo R, Saez-Lopez C, Lecube A, Hernandez C, Manuel Fort J, Selva DM. Adiponectin Upregulates SHBG Production: Molecular Mechanisms and Potential Implications. Endocrinology 2014;155:2820\u201330.","DOI":"10.1210\/en.2014-1072"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_066_w2aab3b7b5b1b6b1ab1b8c66Aa","doi-asserted-by":"crossref","unstructured":"Simo R, Barbosa-Desongles A, Saez-Lopez C, Lecube A, Hernandez C, Selva DM. Molecular Mechanism of TNFalpha-Induced Down-Regulation of SHBG Expression. Mol Endocrinol 2012;26:438\u201346.","DOI":"10.1210\/me.2011-1321"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_067_w2aab3b7b5b1b6b1ab1b8c67Aa","doi-asserted-by":"crossref","unstructured":"Saez-Lopez C, Salcedo-Allende MT, Hernandez C, Simo-Servat O, Simo R, Selva DM. Sex Hormone-Binding Globulin Expression Correlates With Acetyl-Coenzyme A Carboxylase and Triglyceride Content in Human Liver. J Clin Endocrinol Metab 2019;104:1500\u20137.","DOI":"10.1210\/jc.2018-00740"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_068_w2aab3b7b5b1b6b1ab1b8c68Aa","unstructured":"Saez-Lopez C, Barbosa-Desongles A, Hernandez C, Dyer RA, Innis SM, Simo R, et al. Sex Hormone-Binding Globulin Reduction in Metabolic Disorders May Play a Role in NAFLD Development. Endocrinology 2017;158:545\u201359."},{"key":"2023042508114209010_j_jtim-2019-0029_ref_069_w2aab3b7b5b1b6b1ab1b8c69Aa","doi-asserted-by":"crossref","unstructured":"Oike Y, Yasunaga K, Ito Y, Matsumoto S, Maekawa H, Morisada T, et al. Angiopoietin-related growth factor (AGF) promotes epidermal proliferation, remodeling, and regeneration. Proc Natl Acad Sci U S A 2003;100:9494\u20139.","DOI":"10.1073\/pnas.1531901100"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_070_w2aab3b7b5b1b6b1ab1b8c70Aa","doi-asserted-by":"crossref","unstructured":"Ebert T, Kralisch S, Loessner U, Jessnitzer B, Stumvoll M, Fasshauer M, et al. Relationship Between Serum Levels of Angiopoietin-Related Growth Factor and Metabolic Risk Factors. Horm Metab Res 2014;46:685\u201390.","DOI":"10.1055\/s-0034-1382078"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_071_w2aab3b7b5b1b6b1ab1b8c71Aa","doi-asserted-by":"crossref","unstructured":"Ebert T, Bachmann A, Loessner U, Kratzsch J, Blueher M, Stumvoll M, et al. Serum levels of angiopoietin-related growth factor in diabetes mellitus and chronic hemodialysis. Metabolism 2009;58:547\u201351.","DOI":"10.1016\/j.metabol.2008.11.016"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_072_w2aab3b7b5b1b6b1ab1b8c72Aa","doi-asserted-by":"crossref","unstructured":"Namkung J, Koh SB, Kong ID, Choi JW, Yeh BI. Serum levels of angiopoietin-related growth factor are increased in metabolic syndrome. Metabolism 2011;60:564\u20138.","DOI":"10.1016\/j.metabol.2010.05.013"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_073_w2aab3b7b5b1b6b1ab1b8c73Aa","doi-asserted-by":"crossref","unstructured":"Kitazawa M, Ohizumi Y, Oike Y, Hishinuma T, Hashimoto S. Angiopoietin-related growth factor suppresses gluconeogenesis through the akt\/forkhead box class O1-Dependent pathway in Hepatocytes. J Pharmacol Exp Ther 2007;323:787\u201393.","DOI":"10.1124\/jpet.107.127530"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_074_w2aab3b7b5b1b6b1ab1b8c74Aa","doi-asserted-by":"crossref","unstructured":"Pan Q, Fan JG. Noninvasive diagnosis of nonalcoholic steatohepatitis: Emerging approaches. Hepatobiliary Pancreat Dis Int 2019;18:1\u20133.","DOI":"10.1016\/j.hbpd.2018.12.010"},{"key":"2023042508114209010_j_jtim-2019-0029_ref_075_w2aab3b7b5b1b6b1ab1b8c75Aa","doi-asserted-by":"crossref","unstructured":"Lee SW, Lee TY, Yang SS, Tung CF, Yeh HZ, Chang CS, et al. Risk factors and metabolic abnormality of patients with non-alcoholic fatty liver disease: Either non-obese or obese Chinese population. Hepatobiliary Pancreat Dis Int 2018;17:45\u20138.","DOI":"10.1016\/j.hbpd.2018.01.007"}],"container-title":["Journal of Translational Internal Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/content.sciendo.com\/view\/journals\/jtim\/7\/4\/article-p143.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.degruyter.com\/document\/doi\/10.2478\/jtim-2019-0029\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.degruyter.com\/document\/doi\/10.2478\/jtim-2019-0029\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,4,25]],"date-time":"2023-04-25T08:27:55Z","timestamp":1682411275000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.degruyter.com\/document\/doi\/10.2478\/jtim-2019-0029\/html"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12,1]]},"references-count":75,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2019,12,31]]},"published-print":{"date-parts":[[2019,12,1]]}},"alternative-id":["10.2478\/jtim-2019-0029"],"URL":"https:\/\/doi.org\/10.2478\/jtim-2019-0029","relation":{},"ISSN":["2224-4018"],"issn-type":[{"value":"2224-4018","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,12,1]]}}}