{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T13:21:31Z","timestamp":1758892891838,"version":"3.44.0"},"reference-count":39,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2021,12,13]],"date-time":"2021-12-13T00:00:00Z","timestamp":1639353600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2021,12,13]],"date-time":"2021-12-13T00:00:00Z","timestamp":1639353600000},"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":[[2022,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background and Aims<\/jats:title>\n            <jats:p>NASH is a complicated disease characterized by hepatocyte steatosis, inflammation infiltration, and liver fibrosis. Accumulating evidence suggests that the innate immunity plays a key role in NASH progression. Here, we aimed to reveal the role of melanoma differentiation\u2013associated gene 5 (MDA5, also known as Ifih1), a conventional innate immune regulator following viral infection, in the progression of NASH and investigate its underlying mechanism.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results<\/jats:title>\n            <jats:p>We first examined the expression of MDA5 and found that MDA5 was markedly down\u2010regulated in the livers with NASH in human individuals and mice models. MDA5 overexpression significantly inhibits the free fatty acid\u2013induced lipid accumulation and inflammation in hepatocyte in vitro, whereas MDA5\u00a0knockdown promotes hepatocyte lipotoxicity. Using hepatocyte\u2010specific Mda5\u00a0gene knockout and transgenic mice, we found that diet\u2010induced hepatic steatosis, inflammation, and liver fibrosis were markedly exacerbated by Mda5 deficiency but suppressed by Mda5 overexpression. Mechanistically, we found that the activation of apoptosis signal\u2010regulating kinase 1 (ASK1)\u2013mitogen\u2010activated protein kinase pathway was significantly inhibited by MDA5 but enhanced by MDA5 deletion. We further validated that MDA5 directly interacted with ASK1 and suppressed its N\u2010terminal dimerization. Importantly, blockage of ASK1 with adenovirus\u2010expressing dominant negative ASK1 obviously reversed the lipid accumulation and ASK1 pathway activation when Mda5\u00a0was knocked out.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>These data indicate that MDA5 is an essential suppressor in NASH. The findings support MDA5 as a regulator of ASK1 and a promising therapeutic target for NASH.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.32139","type":"journal-article","created":{"date-parts":[[2021,9,5]],"date-time":"2021-09-05T13:22:27Z","timestamp":1630848147000},"page":"924-938","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":10,"title":["Melanoma differentiation\u2014Associated gene 5 protects against NASH in mice"],"prefix":"10.1097","volume":"75","author":[{"given":"Xin","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Cardiology, First Affiliated Hospital, Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education,Gannan Medical University,Ganzhou,China"},{"name":"Gannan Innovation and Translational Medicine Research 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University,Wuhan,China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sha","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Cardiology,Renmin Hospital of Wuhan University,Wuhan,China"},{"name":"Institute of Model Animal,Wuhan University,Wuhan,China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ling","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Cardiology,Renmin Hospital of Wuhan University,Wuhan,China"},{"name":"Institute of Model Animal,Wuhan University,Wuhan,China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tengfei","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Cardiology,Renmin Hospital of Wuhan University,Wuhan,China"},{"name":"Institute of Model Animal,Wuhan University,Wuhan,China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhen","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Cardiology,Renmin Hospital of Wuhan University,Wuhan,China"},{"name":"Institute of Model Animal,Wuhan University,Wuhan,China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan","family":"Wan","sequence":"additional","affiliation":[{"name":"Department of Cardiology,Renmin Hospital of Wuhan University,Wuhan,China"},{"name":"Institute of Model Animal,Wuhan University,Wuhan,China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yiming","family":"Zhong","sequence":"additional","affiliation":[{"name":"Department of Cardiology, First Affiliated Hospital, Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education,Gannan Medical University,Ganzhou,China"},{"name":"Gannan Innovation and Translational Medicine Research Institute,Ganzhou,China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongliang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cardiology,Renmin 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