{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T04:19:14Z","timestamp":1790223554260,"version":"4.1.0"},"reference-count":27,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","license":[{"start":{"date-parts":[[2019,9,27]],"date-time":"2019-09-27T00:00:00Z","timestamp":1569542400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2019,9,27]],"date-time":"2019-09-27T00:00:00Z","timestamp":1569542400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2020,1]]},"abstract":"<jats:p>Sestrin 3 (Sesn3) belongs to the three\u2010member sestrin protein family. Sestrins have been implicated in antioxidative stress, adenosine monophosphate\u2013activated protein kinase and mammalian target of rapamycin signal transduction, and metabolic homeostasis. However, the role of Sesn3 in the development of nonalcoholic steatohepatitis (NASH) has not been previously studied. In this work, we generated <jats:italic toggle=\"yes\">Sesn3<\/jats:italic> whole\u2010body knockout and liver\u2010specific transgenic mice to investigate the hepatic function of Sesn3 in diet\u2010induced NASH. With only 4\u00a0weeks of dietary treatment, <jats:italic toggle=\"yes\">Sesn3<\/jats:italic> knockout mice developed severe NASH phenotype as characterized by hepatic steatosis, inflammation, and fibrosis. Strikingly, after 8\u2010week feeding with a NASH\u2010inducing diet, <jats:italic toggle=\"yes\">Sesn3<\/jats:italic> transgenic mice were largely protected against NASH development. Transcriptomic analysis revealed that multiple extracellular matrix\u2013related processes were up\u2010regulated, including transforming growth factor \u03b2 (TGF\u2010\u03b2) signaling and collagen production. Further biochemical and cell biological analyses have illustrated a critical control of the TGF\u2010\u03b2\u2013mothers against decapentaplegic homolog (Smad) pathway by Sesn3 at the TGF\u2010\u03b2 receptor and Smad3 levels. First, Sesn3 inhibits the TGF\u2010\u03b2 receptor through an interaction with Smad7; second, Sesn3 directly inhibits the Smad3 function through protein\u2013protein interaction and cytosolic retention. <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic> Sesn3 is a critical regulator of the extracellular matrix and hepatic fibrosis by suppression of TGF\u2010\u03b2\u2013Smad3 signaling.<\/jats:p>","DOI":"10.1002\/hep.30820","type":"journal-article","created":{"date-parts":[[2019,6,19]],"date-time":"2019-06-19T10:04:22Z","timestamp":1560938662000},"page":"76-92","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":50,"title":["Sestrin 3 Protects Against Diet\u2010Induced Nonalcoholic Steatohepatitis in Mice Through Suppression of Transforming Growth Factor \u03b2 Signal Transduction"],"prefix":"10.1097","volume":"71","author":[{"given":"Menghao","family":"Huang","sequence":"first","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine,Indiana University School of Medicine,Indianapolis,IN"},{"name":"Department of Biochemistry and Molecular Biology,Indiana University School of Medicine,Indianapolis,IN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyeong Geug","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology,Indiana University School of Medicine,Indianapolis,IN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolin","family":"Zhong","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology,Indiana University School of Medicine,Indianapolis,IN"},{"name":"Department of Gastroenterology,The Affiliated Hospital of Southwest Medical University,Sichuan Province,Luzhou,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuanpeng","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of BioHealth Informatics, School of Informatics and Computing,Indiana University Purdue University Indianapolis,Indianapolis,IN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Zhang","sequence":"additional","affiliation":[{"name":"Carmel High School,Carmel,IN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhigang","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology,Indiana University School of Medicine,Indianapolis,IN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology,Indiana University School of Medicine,Indianapolis,IN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyu","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of BioHealth Informatics, School of Informatics and Computing,Indiana University Purdue University Indianapolis,Indianapolis,IN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romil","family":"Saxena","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine,Indiana University School of Medicine,Indianapolis,IN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunlong","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of BioHealth Informatics, School of Informatics and Computing,Indiana University Purdue University Indianapolis,Indianapolis,IN"},{"name":"Department of Medical and Molecular Genetics,Indiana University School of Medicine,Indianapolis,IN"},{"name":"Center for Computational Biology and Bioinformatics,Indiana University School of Medicine,Indianapolis,IN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of BioHealth Informatics, School of Informatics and Computing,Indiana University Purdue University Indianapolis,Indianapolis,IN"},{"name":"Department of Medical and Molecular Genetics,Indiana University School of Medicine,Indianapolis,IN"},{"name":"Center for Computational Biology and Bioinformatics,Indiana University School of Medicine,Indianapolis,IN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suthat","family":"Liangpunsakul","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine,Indiana University School of Medicine,Indianapolis,IN"},{"name":"Department of Biochemistry and Molecular Biology,Indiana University School of Medicine,Indianapolis,IN"},{"name":"Roudebush Veterans Administration Medical Center,Indianapolis,IN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5452-6882","authenticated-orcid":false,"given":"X. 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