Apolipoprotein CIII Links Hyperlipidemia With Vascular Endothelial Cell Dysfunction

Department of Geriatrics and Vascular Medicine, Life Science and Bioethics Research Center, Tokyo Medical and Dental University, Tokyo, Japan.
Circulation (Impact Factor: 14.43). 09/2008; 118(7):731-42. DOI: 10.1161/CIRCULATIONAHA.108.784785
Source: PubMed


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-beta (PKCbeta). Because PKCbeta 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.
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 PKCbeta in human umbilical vein endothelial cells, resulting in IRS-1 dysfunction via serine phosphorylation. ApoCIII also activated mitogen-activated protein kinase through PKCbeta. The impaired insulin signaling was restored by PKCbeta 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 PKCbeta 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 PKCbeta, which inhibits the IRS-1/PI3K/Akt/eNOS pathway.
Our results suggest that apoCIII is a crucial link between dyslipidemia and insulin resistance in vascular endothelial cells with consequential deleterious effects on their atheroprotective functions.

Full-text preview

Available from:
  • Source
    • "APOC3 stimulated blood-born monocytes and endothelial cells to activate protein kinase C (PKC) and nuclear factor κB (NF-κB) and expression of endothelialproduce vascular cell adhesion molecule-1 (VCAM-1) and intracellular adhesion molecule-1(ICAM-1), and recruitment of monocytes to the vascular wall [16-18]. APOC3 could also activate insulin-resistance pathways in endothelial cells causing endothelial dysfunction [19] and stimulate adipocytes to produce cytokines such as monocyte chemoattractant protein (MCP) 1 and interleukin (IL)6 and suppresses their production of adiponectin [20]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Several polymorphisms in the apolipoprotein C3 (APOC3) gene have been found association with hypertriglyceridemia(HTG), but the link with coronary heart disease(CHD) risk between ethnicities was still controversial. Among them, reseachers paid more attentions to the promoter polymorphisms T-455C and C-482T because both of them located in insulin-responsive element (IRE) and insulin was thought to exert its action by down-regulating APOC3 gene expression. The aim of this study was to investigate the association of the two polymorphisms of APOC3 with CHD in a Han population in East China. TaqMan SNP Genotyping Assays were carried out to detect the genotypes of APOC3 gene, including the T-455C and C-482T, in 286 subjects with CHD and 325 controls without CHD. The levels of serum lipid profiles were also detected by biochemical methods. There was no difference of genotype frequencies and allele frequencies between the CHD population and the controls(P > 0.05). Compared with the most common genotype -455TT or -482CC, the variants had neither significantly increased CHD risk, nor the lipid variables showed any statistically relevant differences in the research population. The adjusted OR of CHD were 5.67 [0.27-18.74] and 0.75 [0.20-2.73] in carriers of the APOC3 -455C and -482T variants, respectively(P > 0.05). There was also no significant difference in APOC3 haplotype distribution in CHD and controls, but there was a strong linkage disequilibrium between T-455C and C-482T with D' = 0.9293, 0.8881, respectively(P < 0.0001). Our data did not support a relationship between the two polymorphisms of APOC3 gene and risk of CHD in the Han population in East China.
    Full-text · Article · Nov 2011 · Lipids in Health and Disease
  • Source
    • "Overexpression of human apo CIII gene in transgenic mice resulted in hypertriglyceridemia (6). Apo CIII has direct athrogenic effect on vascular cells (7). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The Sst-I polymorphic site on the 3' untranslated region of the apo CIII gene, has been previously reported to be associated with hypertriglyceridemia. The aim of the present study was to explore the association between Sst-I polymorphism with plasma lipid and lipoprotein levels in hyperlipidemic (HLP) patients from Semnan province, Iran. Genomic DNA was prepared from 76 patients with HLP and 75 matched healthy subjects. DNA samples were amplified by polymerase chain reaction. The samples were analyzed by restriction fragment length polymorphism (RFLP) method using SstI enzyme. The genotype and allelic frequencies for this polymorphism were significantly different between HLP and normolipidemic groups (P< 0.002). Plasma triglyceride (TG) level was higher in both groups, in S2S2 genotype was more than in the S1S1and S1S2 genotypes, however, there was no significant difference in comparison with the control group. Subjects with S1S2 + S2S2 genotypes in compare to S1S1 genotype had odd ratio of 2.8 (95% CI: 1.41-5.56, P< 0.003) for developing hypertriglyceridemia. The results showed that the presence of rare S2 allele was associated with change in TG level in the selected population.
    Full-text · Article · Feb 2011 · Iranian Journal of Basic Medical Science
  • Source
    • "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 cells77. Plasma levels of apoCIII is a crucial link between dyslipidemia and IR in vascular endothelial cells with consequential deleterious effects on their atheroprotective functions. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Insulin plays an important role in the stimulation of vascular nitric oxide production, with both short term (vasomotility and anti-thrombotic effects) and long term (smooth muscle cell growth and migration inhibition) benefits. Impaired vasodilatory response to insulin, the hallmark of vascular insulin resistance (IR), has important implications for circulatory pathophysiology. An association between adipokines and IR has been observed in both diabetic and nondiabetic states. Adiponectin (APN) is an insulin-sensitizing adipokine known to stimulate skeletal muscle fatty acid (FA) oxidation and reduce lipid accumulation. Recent demonstrations of potential cross-talk between APN and insulin in vascular function regulation are particularly interesting. The lipid accumulation observed after chronic high-fat (HF) diets and in the obese state may reduce vascular response to APN, a pathologic state termed as APN resistance. This review highlights the importance of insulin sensitivity and APN activity in the maintenance of endothelial function. It explores the relationships between vascular IR and APN resistance in the hyperlipidemic pathological condition, representative of the metabolic syndrome. The investigation of vascular insulin and APN resistance provides not only better understanding of vascular pathophysiology, but also an opportunity for therapeutic targeting in individuals affected by the metabolic syndrome.
    Full-text · Article · Oct 2010 · Acta Pharmacologica Sinica
Show more