{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T10:45:11Z","timestamp":1788432311596,"version":"build-2803163510"},"reference-count":46,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2022,10,1]],"date-time":"2022-10-01T00:00:00Z","timestamp":1664582400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Keimyung University Dongsan Medical Center"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Chronic liver inflammation can lead to fibrosis, cirrhosis, and hepatocellular carcinoma. Kupffer cells (KC) secrete proinflammatory and fibrogenic cytokines in response to lipopolysaccharide (LPS), and so play an important role in liver inflammation, where they induce hepatocellular damage. LPS also activates hepatic stellate cells and induces extracellular matrix deposition. In this study, we used isolated primary KC, primary hepatocytes, and primary hepatic stellate cells (HSC) to investigate whether evogliptin directly inhibits inflammatory and fibrotic signaling. We found that evogliptin inhibited LPS-induced secretion of inducible nitric oxide synthase and transforming growth factor \u03b2 (TGF-\u03b2) from KC. Moreover, evogliptin inhibited inflammatory mediator release from hepatocytes and hepatic stellate cell activation that were induced by KC-secreted cytokines. In hepatocytes, evogliptin also inhibited LPS-induced expression of proinflammatory cytokines and fibrotic TGF-\u03b2. In addition, evogliptin inhibited TGF-\u03b2-induced increases in connective tissue growth factor levels and HSC activation. These findings indicate that evogliptin inhibits inflammatory and fibrotic signaling in liver cells. We also showed that the inhibitory effect of evogliptin on inflammatory and fibrotic signaling is associated with the induction of autophagy.<\/jats:p>","DOI":"10.3390\/ijms231911636","type":"journal-article","created":{"date-parts":[[2022,10,8]],"date-time":"2022-10-08T22:19:27Z","timestamp":1665267567000},"page":"11636","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Evogliptin Directly Inhibits Inflammatory and Fibrotic Signaling in Isolated Liver Cells"],"prefix":"10.3390","volume":"23","author":[{"given":"Hye-Young","family":"Seo","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, School of Medicine, Institute for Medical Science, Keimyung University, Daegu 42601, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"So-Hee","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, School of Medicine, Institute for Medical Science, Keimyung University, Daegu 42601, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3237-3317","authenticated-orcid":false,"given":"Eugene","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, School of Medicine, Institute for Medical Science, Keimyung University, Daegu 42601, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae Seok","family":"Hwang","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, School of Medicine, Institute for Medical Science, Keimyung University, Daegu 42601, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sol","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Washington, Seattle, WA 98195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5750-3598","authenticated-orcid":false,"given":"Mi Kyung","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, School of Medicine, Institute for Medical Science, Keimyung University, Daegu 42601, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8950-0866","authenticated-orcid":false,"given":"Byoung Kuk","family":"Jang","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, School of Medicine, Institute for Medical Science, Keimyung University, Daegu 42601, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1002\/hep.27332","article-title":"Hepatic inflammation and fibrosis: Functional links and key pathways","volume":"61","author":"Seki","year":"2015","journal-title":"Hepatology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1002\/hep.1840060430","article-title":"Quantitation, tissue distribution and proliferation kinetics of kupffer cells in normal rat liver","volume":"6","author":"Bouwens","year":"1986","journal-title":"Hepatology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1002\/hep.26607","article-title":"M2 Kupffer cells promote M1 Kupffer cell apoptosis: A protective mechanism against alcoholic and nonalcoholic fatty liver disease","volume":"59","author":"Wan","year":"2014","journal-title":"Hepatology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2651","DOI":"10.4049\/jimmunol.166.4.2651","article-title":"Lipopolysaccharide-induced IL-18 secretion from murine kupffer cells independently of myeloid differentiation factor 88 That is critically involved in induction of production of IL-12 and IL-1\u03b2","volume":"166","author":"Seki","year":"2001","journal-title":"J. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"538","DOI":"10.3389\/fimmu.2016.00538","article-title":"Critical Roles of Kupffer Cells in the Pathogenesis of Alcoholic Liver Disease: From Basic Science to Clinical Trials","volume":"7","author":"Zeng","year":"2016","journal-title":"Front. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.3389\/fimmu.2020.01086","article-title":"Role of Kupffer Cells in Driving Hepatic Inflammation and Fibrosis in HIV Infection","volume":"11","author":"Zhang","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"7413","DOI":"10.3748\/wjg.v12.i46.7413","article-title":"Role of Kupffer cells in the pathogenesis of liver disease","volume":"12","author":"Kolios","year":"2006","journal-title":"World J. Gastroenterol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1188","DOI":"10.1053\/jhep.2003.50472","article-title":"Kupffer cell engulfment of apoptotic bodies stimulates death ligand and cytokine expression","volume":"38","author":"Canbay","year":"2003","journal-title":"Hepatology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1805","DOI":"10.1038\/labinvest.2010.123","article-title":"Kupffer cells are associated with apoptosis, inflammation and fibrotic effects in hepatic fibrosis in rats","volume":"90","author":"Liu","year":"2010","journal-title":"Lab. Investig."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S1386-6346(03)00115-3","article-title":"Connective tissue growth factor (CTGF\/CCN2) in hepatic fibrosis","volume":"26","author":"Rachfal","year":"2003","journal-title":"Hepatol. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1111\/1523-1747.ep12363389","article-title":"Stimulation of Fibroblast Cell Growth, Matrix Production, and Granulation Tissue Formation by Connective Tissue Growth Factor","volume":"107","author":"Frazier","year":"1996","journal-title":"J. Investig. Dermatol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1162","DOI":"10.1111\/j.0022-202X.2005.23750.x","article-title":"Smad3 and Extracellular Signal-Regulated Kinase 1\/2 Coordinately Mediate Transforming Growth Factor-\u03b2-Induced Expression of Connective Tissue Growth Factor in Human Fibroblasts","volume":"124","author":"Leivonen","year":"2005","journal-title":"J. Investig. Dermatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"386","DOI":"10.3389\/fimmu.2015.00386","article-title":"DPP4 in Diabetes","volume":"6","author":"Rohrborn","year":"2015","journal-title":"Front. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1917","DOI":"10.2337\/db10-1707","article-title":"Dipeptidyl peptidase 4 is a novel adipokine potentially linking obesity to the metabolic syndrome","volume":"60","author":"Lamers","year":"2011","journal-title":"Diabetes"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Hirakawa, H., Zempo, H., Ogawa, M., Watanabe, R., Suzuki, J.-I., Akazawa, H., Komuro, I., and Isobe, M. (2015). A DPP-4 inhibitor suppresses fibrosis and inflammation on experimental autoimmune myocarditis in mice. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0119360"},{"key":"ref_16","first-page":"E214","article-title":"DPP-IV inhibitor anagliptin exerts anti-inflammatory effects on macrophages, adipocytes, and mouse livers by suppressing NF-\u03baB activation","volume":"309","author":"Shinjo","year":"2015","journal-title":"Am. J. Physiol. Metab."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1337","DOI":"10.1253\/circj.CJ-12-1168","article-title":"Dipeptidyl peptidase-4 inhibitor, sitagliptin, improves endothelial dysfunction in association with its anti-inflammatory effects in patients with coronary artery disease and uncontrolled diabetes","volume":"77","author":"Matsubara","year":"2013","journal-title":"Circ. J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1186\/s12931-017-0660-4","article-title":"Vildagliptin ameliorates pulmonary fibrosis in lipopolysaccharide-induced lung injury by inhibiting endothelial-to-mesenchymal transition","volume":"18","author":"Suzuki","year":"2017","journal-title":"Respir. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1016\/j.molmet.2017.07.016","article-title":"Elevated hepatic DPP4 activity promotes insulin resistance and non-alcoholic fatty liver disease","volume":"6","author":"Baumeier","year":"2017","journal-title":"Mol. Metab."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1038\/s41598-020-57935-6","article-title":"Dipeptidyl peptidase-4 inhibition prevents nonalcoholic steatohepatitis-associated liver fibrosis and tumor development in mice independently of its anti-diabetic effects","volume":"10","author":"Kawakubo","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1007\/s00795-013-0053-9","article-title":"Linagliptin alleviates hepatic steatosis and inflammation in a mouse model of non-alcoholic steatohepatitis","volume":"47","author":"Klein","year":"2014","journal-title":"Med. Mol. Morphol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1007\/s00535-013-0783-4","article-title":"Dipeptidyl peptidase-4 inhibitor attenuates hepatic fibrosis via suppression of activated hepatic stellate cell in rats","volume":"49","author":"Kaji","year":"2014","journal-title":"J. Gastroenterol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"115246","DOI":"10.1016\/j.taap.2020.115246","article-title":"Vildagliptin, a DPP-4 inhibitor, attenuates carbon tetrachloride-induced liver fibrosis by targeting ERK1\/2, p38\u03b1, and NF-\u03baB signaling","volume":"407","author":"Khalil","year":"2020","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1681","DOI":"10.1111\/dom.12987","article-title":"Efficacy and safety of evogliptin monotherapy in patients with type 2 diabetes and moderately elevated glycated haemoglobin levels after diet and exercise","volume":"19","author":"Park","year":"2017","journal-title":"Diabetes, Obes. Metab."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1111\/dom.14623","article-title":"Efficacy and safety of evogliptin in patients with type 2 diabetes and non-alcoholic fatty liver disease: A multicentre, double-blind, randomized, comparative trial","volume":"24","author":"Han","year":"2022","journal-title":"Diabetes Obes. Metab."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2346","DOI":"10.1111\/jcmm.13526","article-title":"Lipopolysaccharide enhances TGF -\u03b21 signalling pathway and rat pancreatic fibrosis","volume":"22","author":"Sun","year":"2018","journal-title":"J. Cell. Mol. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1369\/0022155415627681","article-title":"TGF-\u03b2\/SMAD Pathway and Its Regulation in Hepatic Fibrosis","volume":"64","author":"Xu","year":"2016","journal-title":"J. Histochem. Cytochem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2018\/8309723","article-title":"Dipeptidyl-Peptidase 4 Inhibitor Sitagliptin Ameliorates Hepatic Insulin Resistance by Modulating Inflammation and Autophagy in ob\/ob Mice","volume":"2018","author":"Zheng","year":"2018","journal-title":"Int. J. Endocrinol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1038\/ncb2021","article-title":"The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1","volume":"12","author":"Komatsu","year":"2010","journal-title":"Nat. Cell Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1080\/08941939.2019.1680777","article-title":"Dipeptidyl Peptidase-4 (DPP-4) Inhibitor Saxagliptin Alleviates Lipopolysaccharide-Induced Acute Lung Injury via Regulating the Nrf-2\/HO-1 and NF-\u03baB Pathways","volume":"34","author":"Guo","year":"2021","journal-title":"J. Investig. Surg."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1538\/expanim.18-0089","article-title":"Linagliptin protects rat carotid artery from balloon injury and activates the NRF2 antioxidant pathway","volume":"68","author":"Si","year":"2019","journal-title":"Exp. Anim."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"130","DOI":"10.3389\/fmed.2020.00130","article-title":"Pro- and Anti-fibrogenic Functions of Gram-Negative Bacterial Lipopolysaccharide in the Liver","volume":"7","author":"Gandhi","year":"2020","journal-title":"Front. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1172\/JCI88881","article-title":"Liver inflammation and fibrosis","volume":"127","author":"Koyama","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Choi, B., Kim, E.-Y., Kim, J.-E., Oh, S., Park, S.-O., Kim, S.-M., Choi, H., Song, J.-K., and Chang, E.-J. (2021). Evogliptin Suppresses Calcific Aortic Valve Disease by Attenuating Inflammation, Fibrosis, and Calcification. Cells, 10.","DOI":"10.3390\/cells10010057"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1016\/j.bcp.2019.08.008","article-title":"Modulation of Sirt1\/NF-\u03baB interaction of evogliptin is attributed to inhibition of vascular inflammatory response leading to attenuation of atherosclerotic plaque formation","volume":"168","author":"Nguyen","year":"2019","journal-title":"Biochem. Pharmacol."},{"key":"ref_36","first-page":"10790","article-title":"Evogliptin attenuates bleomycin-induced lung fibrosis via inhibiting TGF-\u03b2\/Smad signaling in fibroblast","volume":"24","author":"Ba","year":"2020","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"186","DOI":"10.4093\/dmj.2018.0271","article-title":"Evogliptin, a Dipeptidyl Peptidase-4 Inhibitor, Attenuates Renal Fibrosis Caused by Unilateral Ureteral Obstruction in Mice","volume":"44","author":"Kim","year":"2020","journal-title":"Diabetes Metab. J."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"477","DOI":"10.3389\/fimmu.2015.00477","article-title":"Dipeptidyl Peptidase-4 Regulation of SDF-1\/CXCR4 Axis: Implications for Cardiovascular Disease","volume":"6","author":"Zhong","year":"2015","journal-title":"Front. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.jss.2009.10.006","article-title":"Nitric Oxide and Redox Regulation in the Liver: Part II. Redox Biology in Pathologic Hepatocytes and Implications for Intervention","volume":"167","author":"Diesen","year":"2011","journal-title":"J. Surg. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1007\/s00441-011-1246-y","article-title":"TGF-\u03b2 in progression of liver disease","volume":"347","author":"Dooley","year":"2012","journal-title":"Cell Tissue Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1093\/abbs\/gmr028","article-title":"Autophagy process is associated with anti-neoplastic function","volume":"43","author":"Wang","year":"2011","journal-title":"Acta Biochim. Biophys. Sin."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/s40169-017-0154-5","article-title":"Autophagy and inflammation","volume":"6","author":"Qian","year":"2017","journal-title":"Clin. Transl. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"951","DOI":"10.3389\/fphar.2020.00951","article-title":"Detrimental Effect of Sitagliptin Induced Autophagy on Multiterritory Perforator Flap Survival","volume":"11","author":"Chen","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1016\/j.jhep.2019.01.026","article-title":"Autophagy in liver diseases: Time for translation?","volume":"70","author":"Allaire","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Seo, H.-Y., Lee, S.-H., Lee, J.-H., Na Kang, Y., Hwang, J.S., Park, K.-G., Kim, M.K., and Jang, B.K. (2020). Src Inhibition Attenuates Liver Fibrosis by Preventing Hepatic Stellate Cell Activation and Decreasing Connective Tissue Growth Factor. Cells, 9.","DOI":"10.3390\/cells9030558"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1038\/nm.3014","article-title":"Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine","volume":"19","author":"Kim","year":"2013","journal-title":"Nat. Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/19\/11636\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:45:06Z","timestamp":1760143506000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/19\/11636"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,1]]},"references-count":46,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["ijms231911636"],"URL":"https:\/\/doi.org\/10.3390\/ijms231911636","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,1]]}}}