{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T04:35:16Z","timestamp":1791779716155,"version":"4.3.4"},"reference-count":50,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2020,2,7]],"date-time":"2020-02-07T00:00:00Z","timestamp":1581033600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2020,2,7]],"date-time":"2020-02-07T00:00:00Z","timestamp":1581033600000},"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":[[2020,5]]},"abstract":"<jats:sec>\n            <jats:title>Background and Aims<\/jats:title>\n            <jats:p>Dysfunctional hepatic lipid metabolism is a cause of nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disorder worldwide, and is closely associated with insulin resistance and type 2 diabetes. ELOVL fatty acid elongase 6 (Elovl6) is responsible for converting C16 saturated and monounsaturated fatty acids (FAs) into C18 species. We have previously shown that Elovl6 contributes to obesity\u2010induced insulin resistance by modifying hepatic C16\/C18\u2010related FA composition.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results<\/jats:title>\n            <jats:p>To define the precise molecular mechanism by which hepatic Elovl6 affects energy homeostasis and metabolic disease, we generated liver\u2010specific Elovl6 knockout (LKO) mice. Unexpectedly, LKO mice were not protected from high\u2010fat diet\u2013induced insulin resistance. Instead, LKO mice exhibited higher insulin sensitivity than controls when consuming a high\u2010sucrose diet (HSD), which induces lipogenesis. Hepatic patatin\u2010like phospholipase domain\u2010containing protein 3 (Pnpla3) expression was down\u2010regulated in LKO mice, and adenoviral Pnpla3 restoration reversed the enhancement in insulin sensitivity in HSD\u2010fed LKO mice. Lipidomic analyses showed that the hepatic ceramide(d18:1\/18:0) content was lower in LKO mice, which may explain the effect on insulin sensitivity. Ceramide(d18:1\/18:0) enhances protein phosphatase 2A (PP2A) activity by interfering with the binding of PP2A to inhibitor 2 of PP2A, leading to Akt dephosphorylation. Its production involves the formation of an Elovl6\u2013ceramide synthase 4 (CerS4) complex in the endoplasmic reticulum and a Pnpla3\u2013CerS4 complex on lipid droplets. Consistent with this, liver\u2010specific Elovl6 deletion in <jats:italic toggle=\"yes\">ob\/ob<\/jats:italic> mice reduced both hepatic ceramide(d18:1\/18:0) and PP2A activity and ameliorated insulin resistance.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>Our study demonstrates the key role of hepatic Elovl6 in the regulation of the acyl\u2010chain composition of ceramide and that C18:0\u2010ceramide is a potent regulator of hepatic insulin signaling linked to Pnpla3\u2010mediated NAFLD.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.30953","type":"journal-article","created":{"date-parts":[[2019,9,17]],"date-time":"2019-09-17T14:57:27Z","timestamp":1568732247000},"page":"1609-1625","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":66,"title":["Hepatocyte ELOVL Fatty Acid Elongase 6 Determines Ceramide Acyl\u2010Chain Length and Hepatic Insulin Sensitivity in Mice"],"prefix":"10.1097","volume":"71","author":[{"given":"Takashi","family":"Matsuzaka","sequence":"first","affiliation":[{"name":"Department of Internal Medicine (Endocrinology and Metabolism),Faculty of Medicine,University of Tsukuba,Tsukuba,Ibaraki,Japan"},{"name":"Transborder Medical Research Center,University of Tsukuba,Tsukuba,Ibaraki,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Motoko","family":"Kuba","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine (Endocrinology and Metabolism),Faculty of Medicine,University of Tsukuba,Tsukuba,Ibaraki,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saori","family":"Koyasu","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine (Endocrinology and Metabolism),Faculty of Medicine,University of Tsukuba,Tsukuba,Ibaraki,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuta","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Department of Chemistry,Rikkyo University,Toshima,Tokyo,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaori","family":"Motomura","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine (Endocrinology and Metabolism),Faculty of Medicine,University of Tsukuba,Tsukuba,Ibaraki,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sundaram","family":"Arulmozhiraja","sequence":"additional","affiliation":[{"name":"Department of Chemistry,Rikkyo University,Toshima,Tokyo,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Ohno","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine (Endocrinology and Metabolism),Faculty of Medicine,University of Tsukuba,Tsukuba,Ibaraki,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rahul","family":"Sharma","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine (Endocrinology and Metabolism),Faculty of Medicine,University of Tsukuba,Tsukuba,Ibaraki,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuya","family":"Shimura","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine (Endocrinology and Metabolism),Faculty of Medicine,University of Tsukuba,Tsukuba,Ibaraki,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuka","family":"Okajima","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine (Endocrinology and Metabolism),Faculty of Medicine,University of Tsukuba,Tsukuba,Ibaraki,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song\u2010iee","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Internal 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Tsukuba,Tsukuba,Ibaraki,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2143-1921","authenticated-orcid":false,"given":"Hirohito","family":"Sone","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine,Faculty of Medicine,Niigata University,Niigata,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshinori","family":"Takeuchi","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine (Endocrinology and Metabolism),Faculty of Medicine,University of Tsukuba,Tsukuba,Ibaraki,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoya","family":"Yahagi","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine (Endocrinology and Metabolism),Faculty of Medicine,University of Tsukuba,Tsukuba,Ibaraki,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takafumi","family":"Miyamoto","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine (Endocrinology and Metabolism),Faculty of Medicine,University of Tsukuba,Tsukuba,Ibaraki,Japan"},{"name":"Transborder Medical Research Center,University of Tsukuba,Tsukuba,Ibaraki,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Motohiro","family":"Sekiya","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine (Endocrinology and Metabolism),Faculty of Medicine,University of Tsukuba,Tsukuba,Ibaraki,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshimi","family":"Nakagawa","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine (Endocrinology and Metabolism),Faculty of Medicine,University of Tsukuba,Tsukuba,Ibaraki,Japan"},{"name":"International Institute for Integrative Sleep 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Tsukuba,Tsukuba,Ibaraki,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroaki","family":"Tokiwa","sequence":"additional","affiliation":[{"name":"Department of Chemistry,Rikkyo University,Toshima,Tokyo,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hitoshi","family":"Shimano","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine (Endocrinology and Metabolism),Faculty of Medicine,University of Tsukuba,Tsukuba,Ibaraki,Japan"},{"name":"International Institute for Integrative Sleep Medicine,University of Tsukuba,Tsukuba,Ibaraki,Japan"},{"name":"Life Science Center for Survival Dynamics,Tsukuba Advanced Research Alliance,University of Tsukuba,Tsukuba,Ibaraki,Japan"},{"name":"AMED\u2010CREST,Japan Agency for Medical Research and 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