Abstract 14925: Hepatic ERK Protects From Endothelial Dysfunction With The Suppression Of Hepatic Steatosis In Mice Fed High-fat And High-sucrose Diet
Background: Metabolic syndrome (MetS) is characterized by a constellation of disorders, including hypertension, dyslipidemia, hyperglycemia and the accumulation of visceral fat with hepatic steatosis (HST). MetS is a prevalent risk-factor, and the progression of HST is associated with vascular complications. The feature of MetS is insulin resistance in skeletal muscle and liver, caused by metabolic stress, inflammation, oxidative stress and hyperinsulinemia, and all of them activate extracellular regulatory kinase (ERK). However, the role of hepatic ERK in metabolic changes and vascular complications of MetS in vivo have been unknown. The aim of study is to test the impact of deleting hepatic ERK2 on the development of HST and endothelial dysfunction, the most sensitive indicator for vascular complications in MetS.
Methods and Results: Eight-week-old male liver-specific ERK2 knockout mice (LE2KO) and control littermates were fed either a normal diet (ND) or a high-fat/high-sucrose diet (HFHS) for 20 weeks. Serum glucose, homocysteine and peroxide-metabolites (d-ROMs) were measured, and glucose tolerance, insulin sensitivity and histological findings of the liver were tested. Endothelial function was assessed with the isometric tension measurement of aortic rings with acetylcholine (ACh). The liver weight was increased in LE2KO fed HFHS (Control: 1.27±0.05g, LE2KO: 1.69±0.11g, P<0.01, N=12) without changing body weights. LE2KO fed HFHS revealed the marked deterioration of HST. LE2KO fed HFHS demonstrated the impairments of glucose tolerance, insulin resistance, and the mild elevation of serum homocysteine and d-ROMs levels. ACh-induced relaxation was maintained in Control fed HFHS, which was markedly decreased in LE2KO fed HFHS (Control-ND: 67.5±5.2%, Control-HFHS: 59.3±5.2%, LE2KO-ND: 68.7±4.4%, LE2KO-HFHS: 33.2±8.4% with ACh 10-6 M, P<0.01 vs Control-HFHS, N=9-10) without changing nitroprusside-induced relaxations.
Conclusion: Hepatic ERK2 regulates lipid-, glucose- and methionine-metabolism, suppresses the oxidative stress and insulin resistance, and maintains endothelial function with HSHF loading. This study demonstrated an important interaction between hepatic ERK and endothelial function in MetS.
- © 2011 by American Heart Association, Inc.