{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T16:19:18Z","timestamp":1790785158352,"version":"4.1.0"},"reference-count":53,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2013,8,22]]},"abstract":"<jats:sec xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Insulin signaling comprises 2 major cascades: the insulin receptor substrate\/phosphatidylinositol 3\u2032\u2010kinase\/protein kinase B and Ras\/Raf\/mitogen\u2010activated protein kinase\/kinase\/ERK pathways. While many studies on the tissue\u2010specific effects of the insulin receptor substrate\/phosphatidylinositol 3\u2032 \u2010kinase\/protein kinase B pathway have been conducted, the role of the other cascade in tissue\u2010specific insulin resistance has not been investigated. High glucose\/fatty acid toxicity, inflammation, and oxidative stress, all of which are associated with insulin resistance, can activate\n              <jats:styled-content style=\"fixed-case\">ERK<\/jats:styled-content>\n              . The liver plays a central role in metabolism, and hepatosteatosis is associated with vascular diseases. The aim of study was to elucidate the role of hepatic\n              <jats:styled-content style=\"fixed-case\">ERK<\/jats:styled-content>\n              2 in hepatosteatosis, metabolic remodeling, and endothelial dysfunction.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              We created liver\u2010specific ERK2 knockout mice and fed them with a high\u2010fat\/high\u2010sucrose diet for 20\u00a0weeks. The high\u2010fat\/high\u2010sucrose diet\u2013fed liver\u2010specific ERK2 knockout mice exhibited a marked deterioration in hepatosteatosis and metabolic remodeling represented by impairment of glucose tolerance and decreased insulin sensitivity without changes in body weight, blood pressure, and serum cholesterol\/triglyceride levels. In the mice, endoplasmic reticulum stress was induced together with decreased\n              <jats:styled-content style=\"fixed-case\">mRNA<\/jats:styled-content>\n              and protein expressions of hepatic sarco\/endoplasmic reticulum Ca\n              <jats:sup>2+<\/jats:sup>\n              \u2010ATPase 2. In a hepatoma cell line, inhibition of ERK activation\u2013 induced endoplasmic reticulum stress only in the presence of palmitate. Vascular reactive oxygen species were elevated with upregulation of nicotinamide adenine dinucleotide phosphate oxidase1 (Nox1) and Nox4 and decreased phosphorylation of endothelial nitric oxide synthase, which resulted in the remarkable endothelial dysfunction in high\u2010fat\/high\u2010sucrose diet\u2013fed liver\u2010specific ERK2 knockout mice.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Hepatic\n              <jats:styled-content style=\"fixed-case\">ERK<\/jats:styled-content>\n              2 suppresses endoplasmic reticulum stress and hepatosteatosis in vivo, which results in protection from vascular oxidative stress and endothelial dysfunction. These findings demonstrate a novel role of hepatic\n              <jats:styled-content style=\"fixed-case\">ERK<\/jats:styled-content>\n              2 in obese\u2010induced insulin resistance in the protection from hepatovascular metabolic remodeling and vascular diseases.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.113.000361","type":"journal-article","created":{"date-parts":[[2013,8,17]],"date-time":"2013-08-17T04:22:03Z","timestamp":1376713323000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":35,"title":["Hepatic Extracellular Signal\u2013Regulated Kinase 2 Suppresses Endoplasmic Reticulum Stress and Protects From Oxidative Stress and Endothelial Dysfunction"],"prefix":"10.1161","volume":"2","author":[{"given":"Takehiko","family":"Kujiraoka","sequence":"first","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Internal Medicine, National Defense Medical College, Sayama, 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