Apolipoprotein CIII Links Hyperlipidemia With Vascular Endothelial Cell Dysfunction

Abstract

Background-Apolipoprotein CIII (apoCIII) is a component of some triglyceride-rich very-low-density and low-density lipoprotein and is elevated in dyslipidemia with insulin resistance and the metabolic syndrome. We previously reported that apoCIII directly activates proinflammatory and atherogenic signaling in vascular endothelial cells through protein kinase C-␤ (PKC␤). Because PKC␤ impairs the response of vascular endothelial cells to insulin, we tested the hypothesis that apoCIII affects insulin signaling in vascular endothelial cells and its function in vitro and in vivo. Methods and Results-ApoCIII inhibited insulin-induced tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1), decreasing phosphatidylinositol 3-kinase (PI3K)/Akt activation in human umbilical vein endothelial cells. These effects of apoCIII led to reduced endothelial nitric oxide synthase (eNOS) activation and NO release into the media. ApoCIII activated PKC␤ in human umbilical vein endothelial cells, resulting in IRS-1 dysfunction via serine phosphorylation. ApoCIII also activated mitogen-activated protein kinase through PKC␤. The impaired insulin signaling was restored by PKC␤ inhibitor or MEK1 inhibitor. ApoCIII-rich very-low-density lipoprotein and apoCIII impaired insulin signaling in the aorta of C57BL/6J mice and in human umbilical vein endothelial cells, which was recovered by PKC␤ inhibitor. They also inhibited endothelium-dependent relaxation of the aortas of C57BL/6J mice. In summary, apoCIII in very-low-density lipoprotein impaired insulin stimulation of NO production by vascular endothelium and induced endothelial dysfunction in vivo. This adverse effect of apoCIII was mediated by its activation of PKC␤, which inhibits the IRS-1/PI3K/Akt/eNOS pathway. Conclusion-Our

LPL gene variants affect apoC-III response to combination therapy of statins and fenofibric acid in a randomized clinical trial of individuals with mixed dyslipidemia

“…To enhance statistical power, treatment groups of the original studies were collapsed into three major therapy groups: FA alone (n = 226), by guest, on May 11, 2018 www.jlr.org …”

“…Additional evidence of the connection between apoC-III and atherosclerosis comes from an in vitro study suggesting that elevated apoC-III level causes vascular dysfunction ( 30 ). Thus, apoC-III reduction may be one of the pathways by which fi brates decrease atherosclerosis in the mixed dyslipidemia population.…”

Adiponectin resistance and vascular dysfunction in the hyperlipidemic state

“…These signal transduction effects may decrease eNOS activity and NO production. In addition, Apolipoprotein (apo) CIII, a small protein that resides in multiple copies on the surface of very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) [76] , inhibits the IRS-1/PI3K/Akt/eNOS pathway via activation of PKCβ in human umbilical vein endothelial cells [77] . Plasma levels of apoCIII is a crucial link between dyslipidemia and IR in vascular endothelial cells with consequential deleterious effects on their atheroprotective functions.…”

The functional and compositional properties of lipoproteins are altered in patients with metabolic syndrome with increased cholesteryl ester transfer protein activity

“…3A). It is known that apoC-III impairs the lipolysis of TGRL by inhibiting lipoprotein lipase (25), the hepatic uptake of TGRL by the LDL-receptor (26), and vascular endothelial cell dysfunction (27). TG-rich lipoproteins inhibit cholesterol efflux from human macrophage foam cells to lipid-poor apoA-I (21), indicating that the TGRL inhibits arterial reverse cholesterol transport and promote the formation of atherosclerotic lesions.…”