{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T21:53:09Z","timestamp":1769550789599,"version":"3.49.0"},"reference-count":27,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","license":[{"start":{"date-parts":[[2021,10,10]],"date-time":"2021-10-10T00:00:00Z","timestamp":1633824000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2021,10,10]],"date-time":"2021-10-10T00:00:00Z","timestamp":1633824000000},"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":[[2021,12]]},"abstract":"<jats:sec>\n            <jats:title>Background and Aims<\/jats:title>\n            <jats:p>The hepatic mitogen\u2010activated protein kinase (MAPK) cascade leading to c\u2010Jun N\u2010terminal kinase (JNK) activation has been implicated in the pathogenesis of nonalcoholic fatty liver (NAFL)\/NASH. In acute hepatotoxicity, we previously identified a pivotal role for mitochondrial SH3BP5 (SAB; SH3 homology associated BTK binding protein) as a target of JNK, which sustains its activation through promotion of reactive oxygen species production. Therefore, we assessed the role of hepatic SAB in experimental NASH and metabolic syndrome.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results<\/jats:title>\n            <jats:p>In mice fed high\u2010fat, high\u2010calorie, high\u2010fructose (HFHC) diet, SAB expression progressively increased through a sustained JNK\/activating transcription factor 2 (ATF2) activation loop. Inducible deletion of hepatic SAB markedly decreased sustained JNK activation and improved systemic energy expenditure at 8\u00a0weeks followed by decreased body fat at 16\u00a0weeks of HFHC diet. After 30\u00a0weeks, mice treated with control\u2013antisense oligonucleotide (<jats:italic toggle=\"yes\">control\u2010ASO<\/jats:italic>) developed steatohepatitis and fibrosis, which was prevented by <jats:italic toggle=\"yes\">Sab\u2010ASO<\/jats:italic> treatment. Phosphorylated JNK (p\u2010JNK) and phosphorylated ATF2 (p\u2010ATF2) were markedly attenuated by <jats:italic toggle=\"yes\">Sab\u2010ASO<\/jats:italic> treatment. After 52\u00a0weeks of HFHC feeding, control N\u2010acetylgalactosamine antisense oligonucleotide (GalNAc\u2010<jats:italic toggle=\"yes\">Ctl\u2010ASO<\/jats:italic>) treated mice fed the HFHC diet exhibited progression of steatohepatitis and fibrosis, but GalNAc\u2010<jats:italic toggle=\"yes\">Sab\u2010ASO<\/jats:italic> treatment from weeks 40 to 52 reversed these findings while decreasing hepatic SAB, p\u2010ATF2, and p\u2010JNK to chow\u2010fed levels.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>Hepatic SAB expression increases in HFHC diet\u2013fed mice. Deletion or knockdown of SAB inhibited sustained JNK activation and steatohepatitis, fibrosis, and systemic metabolic effects, suggesting that induction of hepatocyte <jats:italic toggle=\"yes\">Sab<\/jats:italic> is an important driver of the interplay between the liver and the systemic metabolic consequences of overfeeding. In established NASH, hepatocyte\u2010targeted GalNAc\u2010<jats:italic toggle=\"yes\">Sab\u2010ASO<\/jats:italic> treatment reversed steatohepatitis and fibrosis.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.32083","type":"journal-article","created":{"date-parts":[[2021,7,31]],"date-time":"2021-07-31T14:13:12Z","timestamp":1627740792000},"page":"3127-3145","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":35,"title":["Hepatic Mitochondrial SAB Deletion or Knockdown Alleviates Diet\u2010Induced Metabolic Syndrome, Steatohepatitis, and Hepatic Fibrosis"],"prefix":"10.1097","volume":"74","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7694-5172","authenticated-orcid":false,"given":"Sanda","family":"Win","sequence":"first","affiliation":[{"name":"USC Research Center for Liver Disease,Keck School of Medicine,University of Southern California,Los Angeles,CA"},{"name":"Division of Gastrointestinal and Liver Disease,Department of Medicine,Keck School of Medicine,University of Southern California,Los Angeles,CA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert W.M.","family":"Min","sequence":"additional","affiliation":[{"name":"Rush University,Rush Medical College,Chicago,IL"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology,Renmin Hospital of Wuhan University,Wuhan,China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gary","family":"Kanel","sequence":"additional","affiliation":[{"name":"USC Research Center for Liver Disease,Keck School of Medicine,University of Southern California,Los Angeles,CA"},{"name":"Department of Pathology,Keck School of Medicine,University of Southern California,Los Angeles,CA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brad","family":"Wanken","sequence":"additional","affiliation":[{"name":"CHLA Saban Research Institute,Los Angeles,CA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yibu","family":"Chen","sequence":"additional","affiliation":[{"name":"USC Libraries Bioinformatics Service,Norris Medical Library,Los Angeles,CA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meng","family":"Li","sequence":"additional","affiliation":[{"name":"USC Libraries Bioinformatics Service,Norris Medical Library,Los Angeles,CA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology,Department of Medicine,Duke University,Durham,NC"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ayako","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology,Department of Medicine,Duke University,Durham,NC"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Filbert W.M.","family":"Aung","sequence":"additional","affiliation":[{"name":"Brown University,Providence,RI"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susan F.","family":"Murray","sequence":"additional","affiliation":[{"name":"Ionis Pharmaceuticals,Carlsbad,CA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mariam","family":"Aghajan","sequence":"additional","affiliation":[{"name":"Ionis Pharmaceuticals,Carlsbad,CA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tin A.","family":"Than","sequence":"additional","affiliation":[{"name":"USC Research Center for Liver Disease,Keck School of Medicine,University of Southern California,Los Angeles,CA"},{"name":"Division of Gastrointestinal and Liver Disease,Department of Medicine,Keck School of Medicine,University of Southern California,Los Angeles,CA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neil","family":"Kaplowitz","sequence":"additional","affiliation":[{"name":"USC Research Center for Liver Disease,Keck School of Medicine,University of Southern California,Los Angeles,CA"},{"name":"Division of Gastrointestinal and Liver Disease,Department of Medicine,Keck School of Medicine,University of Southern California,Los Angeles,CA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","published-online":{"date-parts":[[2021,10,10]]},"reference":[{"key":"hep32083-bib-0001-20250824","article-title":"The role of JNK proteins in metabolism","volume":"2","year":"2010","journal-title":"Sci Transl Med"},{"key":"hep32083-bib-0002-20250824","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1038\/nrgastro.2013.183","article-title":"NAFLD, NASH and liver cancer","volume":"10","year":"2013","journal-title":"Nat Rev Gastroenterol 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History"}},{"value":"2021-07-13","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}