{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T19:37:40Z","timestamp":1768592260039,"version":"3.49.0"},"reference-count":51,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2022,2,22]],"date-time":"2022-02-22T00:00:00Z","timestamp":1645488000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Non-alcoholic steatohepatitis (NASH) is a common chronic liver disease with no decisive treatment. The sodium glucose cotransporter 2 (SGLT2) inhibitor ipragliflozin was developed as a new oral hypoglycemic drug, which can improve NASH via an insulin-independent glucose-lowering effect by inhibiting glucose reabsorption in the renal proximal tubules. However, ipragliflozin appears to modulate steatosis or inflammation via different pathways. To elucidate the new mechanism of ipragliflozin for the treatment of NASH, we evaluated its effects in a NASH mouse model (STAM mice) with beta cell depletion, and compared the expression of microRNAs (miRNAs) in STAM mice treated with or without ipragliflozin (16.7 \u03bcg\/day for 5 weeks). Ipragliflozin reduced aspartate transaminase and alanine aminotransferase levels, along with reduced hepatic steatosis, hepatocyte ballooning, lobular inflammation, and liver fibrosis. In addition, ipragliflozin upregulated mitochondrial transport-related and antioxidant defensive system-related genes in the liver. Among 2555 mouse miRNA probes, miR-19b-3p was commonly differentially expressed with ipragliflozin treatment for 5 weeks in both the liver and serum but in different directions, with a decrease in the liver and increase in the serum. Therefore, ipragliflozin can improve NASH development likely through the antioxidative stress pathway and by regulating miR-19b-3p.<\/jats:p>","DOI":"10.1371\/journal.pone.0261310","type":"journal-article","created":{"date-parts":[[2022,2,22]],"date-time":"2022-02-22T18:32:33Z","timestamp":1645554753000},"page":"e0261310","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":13,"title":["Ipragliflozin attenuates non-alcoholic steatohepatitis development in an animal model"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0760-3045","authenticated-orcid":true,"given":"Asahiro","family":"Morishita","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomoko","family":"Tadokoro","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shintaro","family":"Fujihara","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hisakazu","family":"Iwama","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kyoko","family":"Oura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Koji","family":"Fujita","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joji","family":"Tani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kei","family":"Takuma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mai","family":"Nakahara","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tingting","family":"Shi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Reiji","family":"Haba","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keiichi","family":"Okano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akira","family":"Nishiyama","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masafumi","family":"Ono","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takashi","family":"Himoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tsutomu","family":"Masaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2022,2,22]]},"reference":[{"issue":"1","key":"pone.0261310.ref001","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1002\/hep.28431","article-title":"Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes","volume":"64","author":"ZM Younossi","year":"2016","journal-title":"Hepatology"},{"issue":"9","key":"pone.0261310.ref002","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1111\/j.1464-5491.2005.01582.x","article-title":"Prevalence of non-alcoholic fatty liver disease and its association with impaired glucose metabolism in Japanese adults","volume":"22","author":"S Jimba","year":"2005","journal-title":"Diabet Med"},{"issue":"1","key":"pone.0261310.ref003","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.cld.2013.09.019","article-title":"Obesity and liver disease: the epidemic of the twenty-first century","volume":"18","author":"KE Corey","year":"2014","journal-title":"Clin Liver Dis"},{"issue":"1","key":"pone.0261310.ref004","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.cld.2013.09.018","article-title":"Obesity-associated nonalcoholic fatty liver disease","volume":"18","author":"Y Yilmaz","year":"2014","journal-title":"Clin Liver Dis"},{"issue":"3","key":"pone.0261310.ref005","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1111\/jdi.12645","article-title":"Causes of death in Japanese patients with diabetes based on the results of a survey of 45,708 cases during 2001\u20132010: Report of the Committee on Causes of Death in Diabetes Mellitus","volume":"8","author":"J Nakamura","year":"2017","journal-title":"J Diabetes Investig"},{"issue":"5","key":"pone.0261310.ref006","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1053\/jhep.2003.50193","article-title":"Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference","volume":"37","author":"BA Neuschwander-Tetri","year":"2003","journal-title":"Hepatology"},{"issue":"11","key":"pone.0261310.ref007","doi-asserted-by":"crossref","first-page":"869","DOI":"10.3109\/10715762.2013.837577","article-title":"Involvement of free radicals and oxidative stress in NAFLD\/NASH","volume":"47","author":"Y Sumida","year":"2013","journal-title":"Free Radic Res"},{"issue":"1","key":"pone.0261310.ref008","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/S0168-8278(02)00331-8","article-title":"Serum thioredoxin levels as a predictor of steatohepatitis in patients with nonalcoholic fatty liver disease","volume":"38","author":"Y Sumida","year":"2003","journal-title":"J Hepatol"},{"issue":"4","key":"pone.0261310.ref009","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1053\/j.gastro.2008.06.047","article-title":"Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis","volume":"135","author":"GP Aithal","year":"2008","journal-title":"Gastroenterology"},{"issue":"22","key":"pone.0261310.ref010","doi-asserted-by":"crossref","first-page":"2297","DOI":"10.1056\/NEJMoa060326","article-title":"A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis","volume":"355","author":"R Belfort","year":"2006","journal-title":"N Engl J Med"},{"issue":"2","key":"pone.0261310.ref011","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1006\/bbrc.1999.1403","article-title":"Ursodeoxycholic acid protects hepatocytes against oxidative injury via induction of antioxidants","volume":"263","author":"H Mitsuyoshi","year":"1999","journal-title":"Biochem Biophys Res Commun"},{"issue":"3","key":"pone.0261310.ref012","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1002\/hep.20092","article-title":"Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial","volume":"39","author":"KD Lindor","year":"2004","journal-title":"Hepatology"},{"issue":"4","key":"pone.0261310.ref013","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1111\/hepr.12856","article-title":"Novel antidiabetic medications for non-alcoholic fatty liver disease with type 2 diabetes mellitus","volume":"47","author":"Japan Study Group of N","year":"2017","journal-title":"Hepatol Res"},{"issue":"10019","key":"pone.0261310.ref014","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1016\/S0140-6736(15)00803-X","article-title":"Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study","volume":"387","author":"MJ Armstrong","year":"2016","journal-title":"Lancet"},{"issue":"3","key":"pone.0261310.ref015","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1111\/hepr.12351","article-title":"Pilot study of liraglutide effects in non-alcoholic steatohepatitis and non-alcoholic fatty liver disease with glucose intolerance in Japanese patients (LEAN-J)","volume":"45","author":"Y Eguchi","year":"2015","journal-title":"Hepatol Res"},{"issue":"19","key":"pone.0261310.ref016","doi-asserted-by":"crossref","first-page":"1834","DOI":"10.1056\/NEJMoa1607141","article-title":"Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes","volume":"375","author":"SP Marso","year":"2016","journal-title":"N Engl J Med"},{"issue":"5","key":"pone.0261310.ref017","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/S2213-8587(17)30109-2","article-title":"Semaglutide, lipid-lowering drugs, and NAFLD","volume":"5","author":"N Katsiki","year":"2017","journal-title":"Lancet Diabetes Endocrinol"},{"issue":"3","key":"pone.0261310.ref018","doi-asserted-by":"crossref","first-page":"e0151511","DOI":"10.1371\/journal.pone.0151511","article-title":"Ipragliflozin Improves Hepatic Steatosis in Obese Mice and Liver Dysfunction in Type 2 Diabetic Patients Irrespective of Body Weight Reduction","volume":"11","author":"C Komiya","year":"2016","journal-title":"PLoS One"},{"issue":"6","key":"pone.0261310.ref019","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1111\/j.1872-034X.2010.00644.x","article-title":"Efficacy of ezetimibe for the treatment of non-alcoholic steatohepatitis: An open-label, pilot study","volume":"40","author":"M Yoneda","year":"2010","journal-title":"Hepatol Res"},{"issue":"1","key":"pone.0261310.ref020","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1007\/s00535-010-0291-8","article-title":"Efficacy of long-term ezetimibe therapy in patients with nonalcoholic fatty liver disease","volume":"46","author":"H Park","year":"2011","journal-title":"J Gastroenterol"},{"issue":"4","key":"pone.0261310.ref021","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1002\/hep.27647","article-title":"Ezetimibe for the treatment of nonalcoholic steatohepatitis: assessment by novel magnetic resonance imaging and magnetic resonance elastography in a randomized trial (MOZART trial)","volume":"61","author":"R Loomba","year":"2015","journal-title":"Hepatology"},{"issue":"1","key":"pone.0261310.ref022","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1002\/hep.23276","article-title":"Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis","volume":"51","author":"K Promrat","year":"2010","journal-title":"Hepatology"},{"issue":"7","key":"pone.0261310.ref023","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1038\/nrd3180","article-title":"SGLT2 inhibition\u2014a novel strategy for diabetes treatment","volume":"9","author":"EC Chao","year":"2010","journal-title":"Nat Rev Drug Discov"},{"issue":"2","key":"pone.0261310.ref024","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1152\/physrev.00055.2009","article-title":"Biology of human sodium glucose transporters","volume":"91","author":"EM Wright","year":"2011","journal-title":"Physiol Rev"},{"issue":"1\u20133","key":"pone.0261310.ref025","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/j.ejphar.2013.05.014","article-title":"Effects of SGLT2 selective inhibitor ipragliflozin on hyperglycemia, hyperlipidemia, hepatic steatosis, oxidative stress, inflammation, and obesity in type 2 diabetic mice","volume":"715","author":"A Tahara","year":"2013","journal-title":"Eur J Pharmacol"},{"issue":"1","key":"pone.0261310.ref026","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1254\/jphs.12089FP","article-title":"Antidiabetic effects of SGLT2-selective inhibitor ipragliflozin in streptozotocin-nicotinamide-induced mildly diabetic mice","volume":"120","author":"A Tahara","year":"2012","journal-title":"J Pharmacol Sci"},{"issue":"7","key":"pone.0261310.ref027","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1111\/jphp.12223","article-title":"Effects of sodium-glucose cotransporter 2 selective inhibitor ipragliflozin on hyperglycaemia, oxidative stress, inflammation and liver injury in streptozotocin-induced type 1 diabetic rats","volume":"66","author":"A Tahara","year":"2014","journal-title":"J Pharm Pharmacol"},{"issue":"5740","key":"pone.0261310.ref028","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.1126\/science.1111444","article-title":"Ribo-gnome: the big world of small RNAs","volume":"309","author":"PD Zamore","year":"2005","journal-title":"Science"},{"issue":"5","key":"pone.0261310.ref029","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1038\/ng1536","article-title":"Combinatorial microRNA target predictions","volume":"37","author":"A Krek","year":"2005","journal-title":"Nat Genet"},{"issue":"8","key":"pone.0261310.ref030","doi-asserted-by":"crossref","first-page":"e70744","DOI":"10.1371\/journal.pone.0070744","article-title":"Hepatitis C virus induced miR200c down modulates FAP-1, a negative regulator of Src signaling and promotes hepatic fibrosis","volume":"8","author":"S Ramachandran","year":"2013","journal-title":"PLoS One"},{"issue":"11","key":"pone.0261310.ref031","doi-asserted-by":"crossref","first-page":"1600","DOI":"10.1136\/gutjnl-2011-300717","article-title":"MicroRNA-221\/222 upregulation indicates the activation of stellate cells and the progression of liver fibrosis","volume":"61","author":"T Ogawa","year":"2012","journal-title":"Gut"},{"issue":"12","key":"pone.0261310.ref032","doi-asserted-by":"crossref","first-page":"1753","DOI":"10.1093\/infdis\/jir186","article-title":"Hepatitis C virus infection and hepatic stellate cell activation downregulate miR-29: miR-29 overexpression reduces hepatitis C viral abundance in culture","volume":"203","author":"S Bandyopadhyay","year":"2011","journal-title":"J Infect Dis"},{"issue":"1","key":"pone.0261310.ref033","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1002\/hep.23922","article-title":"Micro-RNA profiling reveals a role for miR-29 in human and murine liver fibrosis","volume":"53","author":"C Roderburg","year":"2011","journal-title":"Hepatology"},{"issue":"5","key":"pone.0261310.ref034","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":"CJ Pirola","year":"2015","journal-title":"Gut"},{"issue":"5","key":"pone.0261310.ref035","doi-asserted-by":"crossref","first-page":"1705","DOI":"10.1053\/gast.2002.36572","article-title":"AGA technical review on nonalcoholic fatty liver disease","volume":"123","author":"AJ Sanyal","year":"2002","journal-title":"Gastroenterology"},{"issue":"4","key":"pone.0261310.ref036","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1053\/jhep.2003.50161","article-title":"Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome","volume":"37","author":"G Marchesini","year":"2003","journal-title":"Hepatology"},{"issue":"6","key":"pone.0261310.ref037","doi-asserted-by":"crossref","first-page":"1649","DOI":"10.1053\/gast.2002.33573","article-title":"Nonalcoholic fatty liver disease","volume":"122","author":"JM Clark","year":"2002","journal-title":"Gastroenterology"},{"issue":"6","key":"pone.0261310.ref038","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1016\/S0016-5085(99)70506-8","article-title":"Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity","volume":"116","author":"CA Matteoni","year":"1999","journal-title":"Gastroenterology"},{"issue":"4","key":"pone.0261310.ref039","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1007\/s00125-011-2446-4","article-title":"Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of randomised trials","volume":"55","author":"G Musso","year":"2012","journal-title":"Diabetologia"},{"issue":"18","key":"pone.0261310.ref040","doi-asserted-by":"crossref","first-page":"1675","DOI":"10.1056\/NEJMoa0907929","article-title":"Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis","volume":"362","author":"AJ Sanyal","year":"2010","journal-title":"N Engl J Med"},{"issue":"10","key":"pone.0261310.ref041","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.1001\/jama.298.10.1180","article-title":"Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials","volume":"298","author":"AM Lincoff","year":"2007","journal-title":"JAMA"},{"key":"pone.0261310.ref042","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.ejphar.2015.02.009","article-title":"Ipragliflozin, an SGLT2 inhibitor, exhibits a prophylactic effect on hepatic steatosis and fibrosis induced by choline-deficient l-amino acid-defined diet in rats","volume":"754","author":"Y Hayashizaki-Someya","year":"2015","journal-title":"Eur J Pharmacol"},{"issue":"4","key":"pone.0261310.ref043","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1016\/j.jhep.2010.11.006","article-title":"Drug-induced toxicity on mitochondria and lipid metabolism: mechanistic diversity and deleterious consequences for the liver","volume":"54","author":"K Begriche","year":"2011","journal-title":"J Hepatol"},{"issue":"1","key":"pone.0261310.ref044","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.mito.2005.10.004","article-title":"Mitochondrial dysfunction in NASH: causes, consequences and possible means to prevent it","volume":"6","author":"K Begriche","year":"2006","journal-title":"Mitochondrion"},{"issue":"6","key":"pone.0261310.ref045","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1016\/j.tplants.2011.03.007","article-title":"ROS signaling: the new wave?","volume":"16","author":"R Mittler","year":"2011","journal-title":"Trends Plant Sci"},{"issue":"2","key":"pone.0261310.ref046","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1002\/hep.24038","article-title":"Relationship between the pattern of hepatic iron deposition and histological severity in nonalcoholic fatty liver disease","volume":"53","author":"JE Nelson","year":"2011","journal-title":"Hepatology"},{"issue":"1","key":"pone.0261310.ref047","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/s40001-020-00408-3","article-title":"Clinical significance of miR-19b-3p in patients with sepsis and its regulatory role in the LPS-induced inflammatory response","volume":"25","author":"H Xu","year":"2020","journal-title":"Eur J Med Res"},{"issue":"1\u20132","key":"pone.0261310.ref048","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1007\/s11010-019-03563-2","article-title":"MiR-19b-3p attenuates IL-1beta induced extracellular matrix degradation and inflammatory injury in chondrocytes by targeting GRK6","volume":"459","author":"L Duan","year":"2019","journal-title":"Mol Cell Biochem"},{"issue":"3","key":"pone.0261310.ref049","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1002\/hep.29885","article-title":"Sphingosine kinase 1 promotes liver fibrosis by preventing miR-19b-3p-mediated inhibition of CCR2","volume":"68","author":"T Lan","year":"2018","journal-title":"Hepatology"},{"issue":"3","key":"pone.0261310.ref050","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1007\/s00795-013-0016-1","article-title":"A murine model for non-alcoholic steatohepatitis showing evidence of association between diabetes and hepatocellular carcinoma","volume":"46","author":"M Fujii","year":"2013","journal-title":"Med Mol Morphol"},{"issue":"2","key":"pone.0261310.ref051","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/j.cld.2015.10.011","article-title":"Histology of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis in Adults and Children","volume":"20","author":"DE Kleiner","year":"2016","journal-title":"Clin Liver Dis"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0261310","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,22]],"date-time":"2022-02-22T18:33:09Z","timestamp":1645554789000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0261310"}},"subtitle":[],"editor":[{"given":"Matias A","family":"Avila","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2022,2,22]]},"references-count":51,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2022,2,22]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0261310","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,22]]}}}