Hepatic Extracellular Signal–Regulated Kinase 2 Suppresses Endoplasmic Reticulum Stress and Protects From Oxidative Stress and Endothelial Dysfunction

Abstract

BackgroundInsulin 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.Methods and ResultsWe 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 Ca2+‐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.ConclusionsHepatic 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.

Inhibition of G-protein-coupled Receptor Kinase 2 Prevents the Dysfunctional Cardiac Substrate Metabolism in Fatty Acid Synthase Transgenic Mice

“…In contrast, the phenotype of wild-type PPARG was less severe and could be (at least partially) rescued by GRK2 inhibition. Together, these data indicate that the ERK axis may specifically counteract the heart failure-promoting transcription factor Pparg by preventing heart failure-related Pparg target gene induction (36,54) and/or could confer protection against palmitate-induced endoplasmic reticulum stress (55).…”

Effect of N-acetyl-l-cysteine on insulin resistance caused by prolonged free fatty acid elevation

“…Short-term IH infusion activates ERK1/2 in the liver (data unpublished) and it has been reported that PKCd activates ERK (Ueda et al 1996). It has also been shown that hepatic ERK2 alleviates oxidative stress, probably as a result of attenuated endoplasmic reticulum (ER) stress (Kujiraoka et al 2013). Short-term lipid infusion also activates p38 MAPK (data unpublished), which has also been reported to attenuate ER stress (Lee et al 2011).…”

TRAIL protects against endothelium injury in diabetes via Akt-eNOS signaling

“…Free radicals or ROS create oxidative stress, which leads to a variety of pathological lesions. Research has revealed that high glucose may activate NADPH oxidase and lead to the production of ROS, which can cause endothelial dysfunction and even cell apoptosis [20,21]. Moreover, previous studies have established that oxygen-derived free radicals interfere with or destroy endothelium by inactivating NO in normal vessels [22,23].…”