title: Hepatic extracellular signal-regulated kinase 2 suppresses endoplasmic reticulum stress and protects from oxidative stress and endothelial dysfunction.
abstract: BACKGROUND
  Insulin signaling comprises 2 major cascades: the insulin receptor substrate/phosphatidylinositol 3'-kinase/protein kinase B and Ras/Raf/mitogen-activated protein kinase/kinase/ERK pathways. While many studies on the tissue-specific effects of the insulin receptor substrate/phosphatidylinositol 3' -kinase/protein kinase B pathway have been conducted, the role of the other cascade in tissue-specific 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 ERK. 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 ERK2 in hepatosteatosis, metabolic remodeling, and endothelial dysfunction.
  
  
  RESULTS
  We created liver-specific ERK2 knockout mice and fed them with a high-fat/high-sucrose diet for 20 weeks. The high-fat/high-sucrose diet-fed liver-specific 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 mRNA and protein expressions of hepatic sarco/endoplasmic reticulum Ca(2+)-ATPase 2. In a hepatoma cell line, inhibition of ERK activation- 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-fat/high-sucrose diet-fed liver-specific ERK2 knockout mice.
  
  
  CONCLUSIONS
  Hepatic ERK2 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 ERK2 in obese-induced insulin resistance in the protection from hepatovascular metabolic remodeling and vascular diseases.
authors: Division of Cardiovascular Medicine, Department of Internal Medicine, National Defense Medical College, Sayama, Japan.
authors: Takehiko
authors: T
authors: Kujiraoka
authors: Yasushi
authors: Y
authors: Satoh
authors: Makoto
authors: M
authors: Ayaori
authors: Yasunaga
authors: Y
authors: Shiraishi
authors: Yuko
authors: Y
authors: Arai-Nakaya
authors: Daihiko
authors: D
authors: Hakuno
authors: Hirotaka
authors: H
authors: Yada
authors: Naruo
authors: N
authors: Kuwada
authors: Shogo
authors: S
authors: Endo
authors: Kikuo
authors: K
authors: Isoda
authors: Takeshi
authors: T
authors: Adachi
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D045744:Cell Line, Tumor; D059305:Diet, High-Fat; D019422:Dietary Sucrose; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004730:Endothelium, Vascular / Q000201:enzymology* / Q000503:physiopathology; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005234:Fatty Liver / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D018149:Glucose Intolerance / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D007328:Insulin / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019255:NADPH Oxidases / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D015398:Signal Transduction; D014652:Vascular Diseases / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control; D014664:Vasodilation
chemical_list: D001786:Blood Glucose; D019422:Dietary Sucrose; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D019255:NADPH Oxidases; C535148:Mapk1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D020930:MAP Kinase Kinase Kinases; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506947:Atp2a2 protein, mouse
keywords: diabetes mellitus; insulin; liver; metabolism; nitric oxide
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