Open AccessHepatic Extracellular Signal–Regulated Kinase 2 Suppresses Endoplasmic Reticulum Stress and Protects From Oxidative Stress and Endothelial Dysfunction
Author(s) -
Kujiraoka Takehiko,
Satoh Yasushi,
Ayaori Makoto,
Shiraishi Yasunaga,
AraiNakaya Yuko,
Hakuno Daihiko,
Yada Hirotaka,
Kuwada Naruo,
Endo Shogo,
Isoda Kikuo,
Adachi Takeshi
Publication year - 2013
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.113.000361
Subject(s) - endoplasmic reticulum , medicine , oxidative stress , microbiology and biotechnology , unfolded protein response , kinase , extracellular , endothelial dysfunction , signal transduction , endocrinology , biology
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 ERK 2 in hepatosteatosis, metabolic remodeling, and endothelial dysfunction. Methods and 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 ERK 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 ERK 2 in obese‐induced insulin resistance in the protection from hepatovascular metabolic remodeling and vascular diseases.