{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T01:56:01Z","timestamp":1777514161390,"version":"3.51.4"},"reference-count":37,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2022,7,31]],"date-time":"2022-07-31T00:00:00Z","timestamp":1659225600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001700","name":"Japanese Ministry of Defense and a MEXT\/JSPS KAKENHI Grant-in-Aid for Scientific Research","doi-asserted-by":"publisher","award":["17K09596"],"award-info":[{"award-number":["17K09596"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001700","name":"Japanese Ministry of Defense and a MEXT\/JSPS KAKENHI Grant-in-Aid for Scientific Research","doi-asserted-by":"publisher","award":["17K09565"],"award-info":[{"award-number":["17K09565"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001700","name":"Japanese Ministry of Defense and a MEXT\/JSPS KAKENHI Grant-in-Aid for Scientific Research","doi-asserted-by":"publisher","award":["JP18H02815"],"award-info":[{"award-number":["JP18H02815"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>We previously demonstrated the marked hepatosteatosis and endothelial dysfunction in hepatocyte-specific ERK2 knockout mice (LE2KO) with a high-fat\/high-sucrose diet (HFHSD), but detailed metabolic changes and the characteristics in insulin-sensitive organs were not tested. This study aimed to characterize metabolic remodeling with changes in insulin-sensitive organs, which could induce endothelial dysfunction in HFHSD-LE2KO. The serum glucose and fatty acid (FA) were modestly higher in HFHSD-LE2KO than HFHSD-Control. FA synthesis genes were up-regulated, which was associated with the decreased phosphorylation of AMPK and ACC, and with the up-regulation of SREBP-1 in the liver from HFHSD-LE2KO. In FA and amino acids fraction analysis, arachidonic acid\/eicosapentaenoic acid ratio, L-ornithine\/arginine ratio, asymmetric dimethylarginine and homocysteine levels were elevated in HFHSD-LE2KO. Insulin-induced phosphorylation of AKT was blunted in skeletal muscle. Serum leptin and IL-1\u03b2 were elevated, and serum adiponectin was decreased with the enlargement of epididymal adipocytes. Finally, the enhanced superoxide levels in the aorta, which were blunted with CCCP, apocynin, and tempol, were observed in HFHSD-LE2KO. A pre-incubation of aortic rings with tempol improved endothelial dysfunction in HFHSD-LE2KO. HFHSD-LE2KO revealed an acceleration of FA synthesis in the liver leading to insulin resistance in skeletal muscle and the enlargement of visceral adipocytes. Global metabolic remodeling such as changes in arginine metabolism, \u03c93\/\u03c96 ratio, and adipocytokines, could affect the vascular oxidative stress and endothelial dysfunction in HFHSD-LE2KO.<\/jats:p>","DOI":"10.3390\/ijms23158521","type":"journal-article","created":{"date-parts":[[2022,8,1]],"date-time":"2022-08-01T02:06:42Z","timestamp":1659319602000},"page":"8521","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Metabolic Remodeling with Hepatosteatosis Induced Vascular Oxidative Stress in Hepatic ERK2 Deficiency Mice with High Fat Diets"],"prefix":"10.3390","volume":"23","author":[{"given":"Takehiko","family":"Kujiraoka","sequence":"first","affiliation":[{"name":"Division of Cardiovascular Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa 359-8513, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuki","family":"Kagami","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa 359-8513, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1347-5115","authenticated-orcid":false,"given":"Toyokazu","family":"Kimura","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa 359-8513, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuki","family":"Ishinoda","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa 359-8513, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5901-4026","authenticated-orcid":false,"given":"Yasunaga","family":"Shiraishi","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa 359-8513, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasuo","family":"Ido","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa 359-8513, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shogo","family":"Endo","sequence":"additional","affiliation":[{"name":"Aging Regulation Research Team, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, 35-2 Sakaecho, Tokyo 173-0015, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0527-6319","authenticated-orcid":false,"given":"Yasushi","family":"Satoh","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, National Defense Medical College, 3-2 Namiki, Tokorozawa 359-8513, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takeshi","family":"Adachi","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa 359-8513, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"154770","DOI":"10.1016\/j.metabol.2021.154770","article-title":"Non-alcoholic fatty liver disease, insulin resistance, metabolic syndrome and their association with vascular risk","volume":"119","author":"Muzurovic","year":"2021","journal-title":"Metabolism"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1190","DOI":"10.1093\/eurheartj\/ehr453","article-title":"Non-alcoholic fatty liver disease: A new and important cardiovascular risk factor?","volume":"33","author":"Bhatia","year":"2012","journal-title":"Eur. 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