{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T00:50:41Z","timestamp":1788828641004,"version":"build-2803163510"},"reference-count":24,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2020,10,22]],"date-time":"2020-10-22T00:00:00Z","timestamp":1603324800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2011\u20100030001"],"award-info":[{"award-number":["2011\u20100030001"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2020R1A2C3008993"],"award-info":[{"award-number":["2020R1A2C3008993"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF\u20102018M3A9C8020027"],"award-info":[{"award-number":["NRF\u20102018M3A9C8020027"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF\u20102020R1I1A1A01070020"],"award-info":[{"award-number":["NRF\u20102020R1I1A1A01070020"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2021,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Nonalcoholic fatty liver disease is a chronic condition involving steatosis, steatohepatitis and fibrosis, and its progression remains unclear. Although the tetraspanin transmembrane 4 L six family member 5 (TM4SF5) is involved in hepatic fibrosis and cancer, its role in nonalcoholic steatohepatitis (NASH) progression is unknown. We investigated the contribution of TM4SF5 to liver pathology using transgenic and KO mice, diet\u2010 or drug\u2010treated mice,\n                    <jats:italic>in vitro<\/jats:italic>\n                    primary cells, and in human tissue. TM4SF5\u2010overexpressing mice exhibited nonalcoholic steatosis and NASH in an age\u2010dependent manner. Initially, TM4SF5\u2010positive hepatocytes and liver tissue exhibited lipid accumulation, decreased Sirtuin 1 (SIRT1), increased sterol regulatory\u2010element binding proteins (SREBPs) and inactive STAT3 via suppressor of cytokine signaling (SOCS)1\/3 upregulation. In older mice, TM4SF5 promoted inflammatory factor induction, SIRT1 expression and STAT3 activity, but did not change SOCS or SREBP levels, leading to active STAT3\u2010mediated ECM production for NASH progression. A TM4SF5\u2010associated increase in chemokines promoted SIRT1 expression and progression to NASH with fibrosis. Suppression of the chemokine CCL20 reduced immune cell infiltration and ECM production. Liver tissue from high\u2010fat diet\u2010 or CCl\n                    <jats:sub>4<\/jats:sub>\n                    \u2010treated mice and human patients exhibited TM4SF5\u2010dependent steatotic or steatohepatitic livers with links between TM4SF5\u2010mediated SIRT1 modulation and SREBP or SOCS\/STAT3 signaling axes. TM4SF5\u2010mediated STAT3 activation in fibrotic NASH livers increased collagen I and laminin \u03b32. Both collagen I \u03b11 and laminin \u03b32 suppression resulted in reduced SIRT1 and active STAT3, but no change in SREBP1 or SOCS, and abolished CCl\n                    <jats:sub>4<\/jats:sub>\n                    \u2010mediated mouse liver damage. TM4SF5\u2010mediated signaling pathways that involve SIRT1, SREBPs and SOCS\/STAT3 promoted progression to NASH. Therefore, TM4SF5 and its downstream effectors may be promising therapeutic targets to treat nonalcoholic fatty liver disease. \u00a9 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.\n                  <\/jats:p>","DOI":"10.1002\/path.5548","type":"journal-article","created":{"date-parts":[[2020,9,22]],"date-time":"2020-09-22T06:33:23Z","timestamp":1600756403000},"page":"55-67","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Differential\n                    <scp>TM4SF5<\/scp>\n                    \u2010mediated\n                    <scp>SIRT1<\/scp>\n                    modulation and metabolic signaling in nonalcoholic steatohepatitis progression"],"prefix":"10.1002","volume":"253","author":[{"given":"Jihye","family":"Ryu","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy Seoul National University  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eunmi","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy Seoul National University  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min\u2010Kyung","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy Seoul National University  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dae\u2010Geun","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy Seoul National University  Seoul Republic of Korea"},{"name":"Systems Biotechnology Research Center, Korea Institute of Science and Technology (KIST)  Gangneung\u2010si Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eun\u2010Ae","family":"Shin","sequence":"additional","affiliation":[{"name":"Department of 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