{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T18:15:44Z","timestamp":1777486544526,"version":"3.51.4"},"reference-count":89,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2020,3,26]],"date-time":"2020-03-26T00:00:00Z","timestamp":1585180800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research Foundation of Korea funded by the Ministry of Education, Inha University","award":["2013R1A6A3A04065825"],"award-info":[{"award-number":["2013R1A6A3A04065825"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Nonalcoholic steatohepatitis (NASH) is defined as a progressive form of nonalcoholic fatty liver disease (NAFLD) and is a common chronic liver disease that causes significant worldwide morbidity and mortality, and has no approved pharmacotherapy. Nevertheless, growing understanding of the molecular mechanisms underlying the development and progression of NASH has suggested multiple potential therapeutic targets and strategies to treat this disease. Here, we review this progress, with emphasis on the functional role of secretory proteins in the development and progression of NASH, in addition to the change of expression of various secretory proteins in mouse NASH models and human NASH subjects. We also highlight secretory protein-based therapeutic approaches that influence obesity-associated insulin resistance, liver steatosis, inflammation, and fibrosis, as well as the gut\u2013liver and adipose\u2013liver axes in the treatment of NASH.<\/jats:p>","DOI":"10.3390\/ijms21072296","type":"journal-article","created":{"date-parts":[[2020,4,1]],"date-time":"2020-04-01T03:44:13Z","timestamp":1585712653000},"page":"2296","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Targeting of Secretory Proteins as a Therapeutic Strategy for Treatment of Nonalcoholic Steatohepatitis (NASH)"],"prefix":"10.3390","volume":"21","author":[{"given":"Kyeongjin","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, College of Medicine, Inha University, Inha-ro 100, Michuhol-gu, Incheon 22212, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kook Hwan","family":"Kim","sequence":"additional","affiliation":[{"name":"Metabolic Diseases Research Center, GI Cell, Inc., B-1014, Tera Tower, Songpa-daero 167, Songpa-gu, Seoul 05855, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,3,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"15080","DOI":"10.1038\/nrdp.2015.80","article-title":"Nonalcoholic fatty liver disease","volume":"1","author":"Brunt","year":"2015","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1038\/nrd.2015.3","article-title":"Non-alcoholic steatohepatitis: Emerging molecular targets and therapeutic strategies","volume":"15","author":"Musso","year":"2016","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Kim, K.H., and Lee, M.S. (2018). Pathogenesis of nonalcoholic steatohepatitis and hormone-based therapeutic approaches. Front. Endocrinol. (Lausanne), 9.","DOI":"10.3389\/fendo.2018.00485"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Niu, L., Geyer, P.E., Wewer Albrechtsen, N.J., Gluud, L.L., Santos, A., Doll, S., Treit, P.V., Holst, J.J., Knop, F.K., and Vilsboll, T. (2019). Plasma proteome profiling discovers novel proteins associated with non-alcoholic fatty liver disease. Mol. Syst. Biol., 15.","DOI":"10.15252\/msb.20188793"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Okubo, H., Kushiyama, A., Nakatsu, Y., Yamamotoya, T., Matsunaga, Y., Fujishiro, M., Sakoda, H., Ohno, H., Yoneda, M., and Asano, T. (2018). Roles of gut-derived secretory factors in the pathogenesis of non-alcoholic fatty liver disease and their possible clinical applications. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19103064"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1836","DOI":"10.1002\/hep.24001","article-title":"Evolution of inflammation in nonalcoholic fatty liver disease: The multiple parallel hits hypothesis","volume":"52","author":"Tilg","year":"2010","journal-title":"Hepatology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1172\/JCI34275","article-title":"Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: Lessons from genetically engineered mice","volume":"118","author":"Postic","year":"2008","journal-title":"J. Clin. Investig."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"210","DOI":"10.3350\/cmh.2013.19.3.210","article-title":"Nonalcoholic fatty liver disease: Molecular mechanisms for the hepatic steatosis","volume":"19","author":"Koo","year":"2013","journal-title":"Clin. Mol. Hepatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"E384","DOI":"10.1152\/ajpendo.00226.2010","article-title":"FATP2 is a hepatic fatty acid transporter and peroxisomal very long-chain acyl-CoA synthetase","volume":"299","author":"Falcon","year":"2010","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1053\/j.gastro.2006.02.006","article-title":"Targeted deletion of FATP5 reveals multiple functions in liver metabolism: Alterations in hepatic lipid homeostasis","volume":"130","author":"Doege","year":"2006","journal-title":"Gastroenterology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1210\/en.2015-1866","article-title":"Hepatocyte-specific disruption of cd36 attenuates fatty liver and improves insulin sensitivity in HFD-fed mice","volume":"157","author":"Wilson","year":"2016","journal-title":"Endocrinology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.cmet.2007.12.009","article-title":"Selective versus total insulin resistance: A pathogenic paradox","volume":"7","author":"Brown","year":"2008","journal-title":"Cell Metab."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Kim, K., Qiang, L., Hayden, M.S., Sparling, D.P., Purcell, N.H., and Pajvani, U.B. (2016). mTORC1-independent Raptor prevents hepatic steatosis by stabilizing PHLPP2. Nat. Commun., 7.","DOI":"10.1038\/ncomms10255"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1568","DOI":"10.1053\/j.gastro.2017.08.039","article-title":"Degradation of PHLPP2 by KCTD17, via a glucagon-dependent pathway, promotes hepatic steatosis","volume":"153","author":"Kim","year":"2017","journal-title":"Gastroenterology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1053\/j.gastro.2013.11.049","article-title":"Increased de novo lipogenesis is a distinct characteristic of individuals with nonalcoholic fatty liver disease","volume":"146","author":"Lambert","year":"2014","journal-title":"Gastroenterology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2335","DOI":"10.1111\/j.1572-0241.2003.07725.x","article-title":"Hepatic mitochondrial beta-oxidation in patients with nonalcoholic steatohepatitis assessed by 13C-octanoate breath test","volume":"98","author":"Miele","year":"2003","journal-title":"Am. J. Gastroenterol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1625","DOI":"10.1136\/gutjnl-2012-302789","article-title":"Whole-body substrate metabolism is associated with disease severity in patients with non-alcoholic fatty liver disease","volume":"62","author":"Croci","year":"2013","journal-title":"Gut"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1007\/s00535-013-0758-5","article-title":"Mechanisms of hepatic triglyceride accumulation in non-alcoholic fatty liver disease","volume":"48","author":"Kawano","year":"2013","journal-title":"J. Gastroenterol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.numecd.2008.12.015","article-title":"Hepatic lipid metabolism and non-alcoholic fatty liver disease","volume":"19","author":"Tessari","year":"2009","journal-title":"Nutr. Metab. Cardiovasc. Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1659","DOI":"10.1001\/jama.2011.520","article-title":"Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: The TONIC randomized controlled trial","volume":"305","author":"Lavine","year":"2011","journal-title":"JAMA"},{"key":"ref_21","first-page":"559","article-title":"Effect of resveratrol on non-alcoholic fatty liver disease","volume":"18","author":"Theodotou","year":"2019","journal-title":"Exp. Ther. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.pharmthera.2017.05.011","article-title":"Targeting nuclear receptors for the treatment of fatty liver disease","volume":"179","author":"Tanaka","year":"2017","journal-title":"Pharmacol. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1136\/gutjnl-2017-315691","article-title":"Non-alcoholic steatohepatitis pathogenesis: Sublethal hepatocyte injury as a driver of liver inflammation","volume":"67","author":"Ibrahim","year":"2018","journal-title":"Gut"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1038\/s41575-018-0082-x","article-title":"The role of macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis","volume":"16","author":"Kazankov","year":"2019","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1007\/s12072-013-9468-6","article-title":"Immune and inflammatory pathways in NASH","volume":"7","author":"Ganz","year":"2013","journal-title":"Hepatol. Int."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"G1324","DOI":"10.1152\/ajpgi.90564.2008","article-title":"Interleukin-1 participates in the progression from liver injury to fibrosis","volume":"296","author":"Gieling","year":"2009","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1016\/j.jhep.2017.01.022","article-title":"NLRP3 inflammasome blockade reduces liver inflammation and fibrosis in experimental NASH in mice","volume":"66","author":"Mridha","year":"2017","journal-title":"J. Hepatol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Azzu, V., Vacca, M., Virtue, S., Allison, M., and Vidal-Puig, A. (2020). Adipose tissue-liver cross talk in the control of whole-body metabolism: Implications in non-alcoholic fatty liver disease. Gastroenterology.","DOI":"10.1053\/j.gastro.2019.12.054"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/j.jhep.2017.11.014","article-title":"Lipotoxicity and the gut-liver axis in NASH pathogenesis","volume":"68","author":"Marra","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1136\/gutjnl-2016-313654","article-title":"Adipose tissue macrophages induce hepatic neutrophil recruitment and macrophage accumulation in mice","volume":"67","author":"Bijnen","year":"2018","journal-title":"Gut"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1038\/nri.2017.10","article-title":"Neutrophils as protagonists and targets in chronic inflammation","volume":"17","author":"Soehnlein","year":"2017","journal-title":"Nat. Rev. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"33","DOI":"10.3803\/EnM.2018.33.1.33","article-title":"Association of adipokines with development and progression of nonalcoholic fatty liver disease","volume":"33","author":"Boutari","year":"2018","journal-title":"Endocrinol. Metab. (Seoul)"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1016\/j.jhep.2016.01.025","article-title":"Metabolic interplay between white, beige, brown adipocytes and the liver","volume":"64","author":"Scheja","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1038\/s41374-018-0120-x","article-title":"Activation of brown adipose tissue enhances the efficacy of caloric restriction for treatment of nonalcoholic steatohepatitis","volume":"99","author":"Poekes","year":"2019","journal-title":"Lab. Investig."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Kolodziejczyk, A.A., Zheng, D., Shibolet, O., and Elinav, E. (2019). The role of the microbiome in NAFLD and NASH. EMBO Mol. Med., 11.","DOI":"10.15252\/emmm.201809302"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1111\/j.1478-3231.2008.01723.x","article-title":"Susceptibility to gut leakiness: A possible mechanism for endotoxaemia in non-alcoholic steatohepatitis","volume":"28","author":"Farhadi","year":"2008","journal-title":"Liver Int."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1002\/hep.26319","article-title":"Intestinal microbiota in patients with nonalcoholic fatty liver disease","volume":"58","author":"Mouzaki","year":"2013","journal-title":"Hepatology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1002\/hep.28356","article-title":"The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota","volume":"63","author":"Boursier","year":"2016","journal-title":"Hepatology"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"13493","DOI":"10.3748\/wjg.v20.i37.13493","article-title":"Recent insights into farnesoid X receptor in non-alcoholic fatty liver disease","volume":"20","author":"Xu","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Han, C.Y. (2018). Update on FXR biology: Promising therapeutic target?. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19072069"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1038\/nrgastro.2017.38","article-title":"Mechanisms of hepatic stellate cell activation","volume":"14","author":"Tsuchida","year":"2017","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2380","DOI":"10.1002\/hep.30093","article-title":"High mobility group box-1 drives fibrosis progression signaling via the receptor for advanced Glycation end products in mice","volume":"68","author":"Ge","year":"2018","journal-title":"Hepatology"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1711","DOI":"10.1002\/hep.25559","article-title":"Hedgehog pathway activation parallels histologic severity of injury and fibrosis in human nonalcoholic fatty liver disease","volume":"55","author":"Guy","year":"2012","journal-title":"Hepatology"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Zhu, C., Kim, K., Wang, X., Bartolome, A., Salomao, M., Dongiovanni, P., Meroni, M., Graham, M.J., Yates, K.P., and Diehl, A.M. (2018). Hepatocyte Notch activation induces liver fibrosis in nonalcoholic steatohepatitis. Sci. Transl. Med., 10.","DOI":"10.1126\/scitranslmed.aat0344"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Yang, Y.M., Noureddin, M., Liu, C., Ohashi, K., Kim, S.Y., Ramnath, D., Powell, E.E., Sweet, M.J., Roh, Y.S., and Hsin, I.F. (2019). Hyaluronan synthase 2-mediated hyaluronan production mediates Notch1 activation and liver fibrosis. Sci. Transl. Med., 11.","DOI":"10.1126\/scitranslmed.aat9284"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1016\/j.cmet.2016.09.016","article-title":"Hepatocyte TAZ\/WWTR1 promotes inflammation and fibrosis in nonalcoholic steatohepatitis","volume":"24","author":"Wang","year":"2016","journal-title":"Cell Metab."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Schwabe, R.F., Tabas, I., and Pajvani, U.B. (2020). Mechanisms of fibrosis development in NASH. Gastroenterology.","DOI":"10.1053\/j.gastro.2019.11.311"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.1053\/j.gastro.2018.07.006","article-title":"Simtuzumab is ineffective for patients with bridging fibrosis or compensated cirrhosis caused by nonalcoholic steatohepatitis","volume":"155","author":"Harrison","year":"2018","journal-title":"Gastroenterology"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"5060","DOI":"10.1073\/pnas.0511167103","article-title":"Galectin-3 regulates myofibroblast activation and hepatic fibrosis","volume":"103","author":"Henderson","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1038\/s41574-018-0016-2","article-title":"Glucagon-like peptide 1 in health and disease","volume":"14","author":"Andersen","year":"2018","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3346","DOI":"10.2337\/db14-0302","article-title":"GLP-1 agonism stimulates brown adipose tissue thermogenesis and browning through hypothalamic AMPK","volume":"63","author":"Beiroa","year":"2014","journal-title":"Diabetes"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"More, V.R., Lao, J., McLaren, D.G., Cumiskey, A.M., Murphy, B.A., Chen, Y., Previs, S., Stout, S., Patel, R., and Satapati, S. (2017). Glucagon like receptor 1\/glucagon dual agonist acutely enhanced hepatic lipid clearance and suppressed de novo lipogenesis in mice. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0186586"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"G762","DOI":"10.1152\/ajpgi.00476.2011","article-title":"Glucagon-like peptide-1 receptor agonism improves metabolic, biochemical, and histopathological indices of nonalcoholic steatohepatitis in mice","volume":"302","author":"Trevaskis","year":"2012","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"16461","DOI":"10.1038\/s41598-018-33949-z","article-title":"Differential effects of a glucagon-like peptide 1 receptor agonist in non-alcoholic fatty liver disease and in response to hepatectomy","volume":"8","author":"Valdecantos","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/j.jhep.2015.08.038","article-title":"Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatohepatitis","volume":"64","author":"Armstrong","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1159\/000491763","article-title":"Effects of a DPP4 inhibitor on progression of NASH-related HCC and the p62\/Keap1\/Nrf2-pentose phosphate pathway in a mouse model","volume":"8","author":"Kawaguchi","year":"2019","journal-title":"Liver Cancer"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1396","DOI":"10.12669\/pjms.326.11133","article-title":"Vildagliptin ameliorates biochemical, metabolic and fatty changes associated with Non Alcoholic fatty liver disease","volume":"32","author":"Hussain","year":"2016","journal-title":"Pak. J. Med. Sci."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2258","DOI":"10.2337\/db09-0278","article-title":"Glucagon-like peptide 1\/glucagon receptor dual agonism reverses obesity in mice","volume":"58","author":"Pocai","year":"2009","journal-title":"Diabetes"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1038\/nm.3761","article-title":"A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents","volume":"21","author":"Finan","year":"2015","journal-title":"Nat. Med."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1016\/j.molmet.2017.02.002","article-title":"Monomeric GLP-1\/GIP\/glucagon triagonism corrects obesity, hepatosteatosis, and dyslipidemia in female mice","volume":"6","author":"Jall","year":"2017","journal-title":"Mol. Metab."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"950","DOI":"10.1002\/hep.28962","article-title":"A novel glucagon-like peptide 1\/glucagon receptor dual agonist improves steatohepatitis and liver regeneration in mice","volume":"65","author":"Valdecantos","year":"2017","journal-title":"Hepatology"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.pharmthera.2019.02.008","article-title":"Growth differentiation factor 15 (GDF15): A survival protein with therapeutic potential in metabolic diseases","volume":"198","author":"Baek","year":"2019","journal-title":"Pharmacol. Ther."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"276","DOI":"10.5009\/gnl16049","article-title":"Growth differentiation factor 15 predicts chronic liver disease severity","volume":"11","author":"Lee","year":"2017","journal-title":"Gut Liver"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Liu, X., Chi, X., Gong, Q., Gao, L., Niu, Y., Chi, X., Cheng, M., Si, Y., Wang, M., and Zhong, J. (2015). Association of serum level of growth differentiation factor 15 with liver cirrhosis and hepatocellular carcinoma. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0127518"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1016\/j.cmet.2018.12.016","article-title":"GDF15 provides an endocrine signal of nutritional stress in mice and humans","volume":"29","author":"Patel","year":"2019","journal-title":"Cell Metab."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"6789","DOI":"10.1038\/s41598-018-25098-0","article-title":"Growth differentiation factor 15 ameliorates nonalcoholic steatohepatitis and related metabolic disorders in mice","volume":"8","author":"Kim","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"17238","DOI":"10.1038\/s41598-017-17574-w","article-title":"GDF15 deficiency exacerbates chronic alcohol- and carbon tetrachloride-induced liver injury","volume":"7","author":"Chung","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/j.bbrc.2018.04.061","article-title":"CST3 and GDF15 ameliorate renal fibrosis by inhibiting fibroblast growth and activation","volume":"500","author":"Kim","year":"2018","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1038\/s41419-018-0530-0","article-title":"Epithelial cell-derived cytokines CST3 and GDF15 as potential therapeutics for pulmonary fibrosis","volume":"9","author":"Kim","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1210\/er.2018-00134","article-title":"Fibroblast growth factor 15\/19: From basic functions to therapeutic perspectives","volume":"39","author":"Somm","year":"2018","journal-title":"Endocr. Rev."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1621","DOI":"10.1126\/science.1198363","article-title":"FGF19 as a postprandial, insulin-independent activator of hepatic protein and glycogen synthesis","volume":"331","author":"Kir","year":"2011","journal-title":"Science"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1818","DOI":"10.1136\/gutjnl-2016-312975","article-title":"Fibroblast growth factor 15\/19 (FGF15\/19) protects from diet-induced hepatic steatosis: Development of an FGF19-based chimeric molecule to promote fatty liver regeneration","volume":"66","author":"Uriarte","year":"2017","journal-title":"Gut"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"2594","DOI":"10.1210\/en.2003-1671","article-title":"Fibroblast growth factor 19 increases metabolic rate and reverses dietary and leptin-deficient diabetes","volume":"145","author":"Fu","year":"2004","journal-title":"Endocrinology"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1002\/hep4.1108","article-title":"Engineered FGF19 eliminates bile acid toxicity and lipotoxicity leading to resolution of steatohepatitis and fibrosis in mice","volume":"1","author":"Zhou","year":"2017","journal-title":"Hepatol. Commun."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Alisi, A., Ceccarelli, S., Panera, N., Prono, F., Petrini, S., De Stefanis, C., Pezzullo, M., Tozzi, A., Villani, A., and Bedogni, G. (2013). Association between serum atypical fibroblast growth factors 21 and 19 and pediatric nonalcoholic fatty liver disease. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0067160"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"G440","DOI":"10.1152\/ajpgi.00322.2009","article-title":"The hepatic response to FGF19 is impaired in patients with nonalcoholic fatty liver disease and insulin resistance","volume":"298","author":"Schreuder","year":"2010","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1174","DOI":"10.1016\/S0140-6736(18)30474-4","article-title":"NGM282 for treatment of non-alcoholic steatohepatitis: A multicentre, randomised, double-blind, placebo-controlled, phase 2 trial","volume":"391","author":"Harrison","year":"2018","journal-title":"Lancet"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1172\/JCI23606","article-title":"FGF-21 as a novel metabolic regulator","volume":"115","author":"Kharitonenkov","year":"2005","journal-title":"J. Clin. Investig."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"245","DOI":"10.4093\/dmj.2014.38.4.245","article-title":"FGF21 as a stress hormone: The roles of FGF21 in stress adaptation and the treatment of metabolic diseases","volume":"38","author":"Kim","year":"2014","journal-title":"Diabetes Metab. J."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"250","DOI":"10.2337\/db08-0392","article-title":"Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice","volume":"58","author":"Xu","year":"2009","journal-title":"Diabetes"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1007\/s00125-014-3475-6","article-title":"Fibroblast growth factor 21 participates in adaptation to endoplasmic reticulum stress and attenuates obesity-induced hepatic metabolic stress","volume":"58","author":"Kim","year":"2015","journal-title":"Diabetologia"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1002\/oby.22344","article-title":"Pegbelfermin (BMS-986036), PEGylated FGF21, in patients with obesity and type 2 diabetes: Results from a randomized phase 2 study","volume":"27","author":"Charles","year":"2019","journal-title":"Obesity (Silver Spring)"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1053\/j.gastro.2014.07.044","article-title":"Fibroblast growth factor 21 limits lipotoxicity by promoting hepatic fatty acid activation in mice on methionine and choline-deficient diets","volume":"147","author":"Fisher","year":"2014","journal-title":"Gastroenterology"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"3379","DOI":"10.1111\/bph.14383","article-title":"A long-acting FGF21 alleviates hepatic steatosis and inflammation in a mouse model of non-alcoholic steatohepatitis partly through an FGF21-adiponectin-IL17A pathway","volume":"175","author":"Bao","year":"2018","journal-title":"Br. J. Pharmacol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.taap.2015.11.012","article-title":"Fibroblast growth factor 21 attenuates hepatic fibrogenesis through TGF-beta\/smad2\/3 and NF-kappaB signaling pathways","volume":"290","author":"Xu","year":"2016","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"2705","DOI":"10.1016\/S0140-6736(18)31785-9","article-title":"Pegbelfermin (BMS-986036), a PEGylated fibroblast growth factor 21 analogue, in patients with non-alcoholic steatohepatitis: A randomised, double-blind, placebo-controlled, phase 2a trial","volume":"392","author":"Sanyal","year":"2019","journal-title":"Lancet"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/j.cmet.2015.02.009","article-title":"The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance","volume":"21","author":"Lee","year":"2015","journal-title":"Cell Metab."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Muzumdar, R.H., Huffman, D.M., Atzmon, G., Buettner, C., Cobb, L.J., Fishman, S., Budagov, T., Cui, L., Einstein, F.H., and Poduval, A. (2009). Humanin: A novel central regulator of peripheral insulin action. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0006334"},{"key":"ref_89","first-page":"796","article-title":"Naturally occurring mitochondrial-derived peptides are age-dependent regulators of apoptosis, insulin sensitivity, and inflammatory markers","volume":"8","author":"Cobb","year":"2016","journal-title":"Aging (Albany N.Y.)"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/7\/2296\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:12:06Z","timestamp":1760173926000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/7\/2296"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,26]]},"references-count":89,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2020,4]]}},"alternative-id":["ijms21072296"],"URL":"https:\/\/doi.org\/10.3390\/ijms21072296","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,26]]}}}