{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T19:52:45Z","timestamp":1792093965741,"version":"4.4.0"},"reference-count":43,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2021,5,22]],"date-time":"2021-05-22T00:00:00Z","timestamp":1621641600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2021,5,22]],"date-time":"2021-05-22T00:00:00Z","timestamp":1621641600000},"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":[[2021,9]]},"abstract":"<jats:sec>\n                    <jats:title>Background and Aims<\/jats:title>\n                    <jats:p>\n                      Human transmembrane 6 superfamily 2 (\n                      <jats:italic toggle=\"yes\">TM6SF2<\/jats:italic>\n                      ) variant rs58542926 is associated with NAFLD and HCC. However, conflicting reports in germline\n                      <jats:italic toggle=\"yes\">Tm6sf2<\/jats:italic>\n                      knockout mice suggest no change or decreased very low density lipoprotein (VLDL) secretion and either unchanged or increased hepatic steatosis, with no increased fibrosis. We generated liver\u2010specific\n                      <jats:italic toggle=\"yes\">Tm6Sf2<\/jats:italic>\n                      knockout mice (Tm6 LKO) to study VLDL secretion and the impact on development and progression of NAFLD.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Approach and Results<\/jats:title>\n                    <jats:p>Two independent lines of Tm6 LKO mice exhibited spontaneous hepatic steatosis. Targeted lipidomic analyses showed increased triglyceride species whose distribution and abundance phenocopied findings in mice with liver\u2010specific deletion of microsomal triglyceride transfer protein. The VLDL triglyceride secretion was reduced with small, underlipidated particles and unchanged or increased apolipoprotein B. Liver\u2010specific adeno\u2010associated viral, serotype 8 (AAV8) rescue using either wild\u2010type or mutant E167K\u2010Tm6 reduced hepatic steatosis and improved VLDL secretion. The Tm6 LKO mice fed a high milk\u2010fat diet for 3\u00a0weeks exhibited increased steatosis and fibrosis, and those phenotypes were further exacerbated when mice were fed fibrogenic, high fat\/fructose diets for 20\u00a0weeks. In two models of HCC, either neonatal mice injected with streptozotocin (NASH\/STAM) and high\u2010fat fed or with diethylnitrosamine injection plus fibrogenic diet feeding, Tm6 LKO mice exhibited increased steatosis, greater tumor burden, and increased tumor area versus Tm6 flox controls. Additionally, diethylnitrosamine\u2010injected and fibrogenic diet\u2013fed Tm6 LKO mice administered wild\u2010type Tm6 or E167K\u2010mutant Tm6 AAV8 revealed significant tumor attenuation, with tumor burden inversely correlated with Tm6 protein levels.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Liver\u2010specific\n                      <jats:italic toggle=\"yes\">Tm6sf2<\/jats:italic>\n                      deletion impairs VLDL secretion, promoting hepatic steatosis, fibrosis, and accelerated development of HCC, which was mitigated with AAV8\u2010 mediated rescue.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/hep.31771","type":"journal-article","created":{"date-parts":[[2021,2,27]],"date-time":"2021-02-27T11:37:02Z","timestamp":1614425822000},"page":"1203-1219","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":106,"title":["Liver\u2010Specific Deletion of Mouse Tm6sf2 Promotes Steatosis, Fibrosis, and Hepatocellular Cancer"],"prefix":"10.1097","volume":"74","author":[{"given":"Elizabeth P.","family":"Newberry","sequence":"first","affiliation":[{"name":"Department of Medicine,Washington University School of Medicine,St. Louis,MO,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zoe","family":"Hall","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Cambridge Systems Biology Centre,University of Cambridge,Cambridge,United Kingdom"},{"name":"Division of Systems Medicine,Department of Metabolism, Digestion and Reproduction,Biomolecular Medicine,Imperial College London,London,United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Medicine,Washington University School of Medicine,St. Louis,MO,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth A.","family":"Molitor","sequence":"additional","affiliation":[{"name":"Department of Medicine,Washington University School of Medicine,St. Louis,MO,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter O.","family":"Bayguinov","sequence":"additional","affiliation":[{"name":"Washington University Center for Cellular Imaging,St. Louis,MO,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory W.","family":"Strout","sequence":"additional","affiliation":[{"name":"Washington University Center for Cellular Imaging,St. Louis,MO,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James A.J.","family":"Fitzpatrick","sequence":"additional","affiliation":[{"name":"Washington University Center for Cellular Imaging,St. Louis,MO,USA"},{"name":"Departments of Cell Biology & Physiology and Neuroscience,Washington University School of Medicine,St. Louis,MO,USA"},{"name":"Department of Biomedical Engineering,Washington University in Saint Louis,St. Louis,MO,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth M.","family":"Brunt","sequence":"additional","affiliation":[{"name":"Pathology and Immunology,Washington University School of Medicine,St. Louis,MO,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian L.","family":"Griffin","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Cambridge Systems Biology Centre,University of Cambridge,Cambridge,United Kingdom"},{"name":"Division of Systems Medicine,Department of Metabolism, Digestion and Reproduction,Biomolecular Medicine,Imperial College London,London,United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas O.","family":"Davidson","sequence":"additional","affiliation":[{"name":"Department of Medicine,Washington University School of Medicine,St. Louis,MO,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2021,5,22]]},"reference":[{"key":"hep31771-bib-0001-20250824","doi-asserted-by":"crossref","first-page":"1851","DOI":"10.1053\/j.gastro.2020.01.052","article-title":"Nonalcoholic fatty liver disease 2020: the state of the disease","volume":"158","year":"2020","journal-title":"Gastroenterology"},{"key":"hep31771-bib-0002-20250824","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1002\/hep.31229","article-title":"Genetic pathways in nonalcoholic fatty liver disease: insights from systems 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