Apolipoprotein CIII links hyperlipidemia with vascular endothelial cell dysfunction

Area of Science:

• Cardiovascular Biology
• Endocrinology
• Metabolic Syndrome Research

Background:

• Apolipoprotein CIII (apoCIII) is linked to dyslipidemia, insulin resistance, and metabolic syndrome.
• Previous work showed apoCIII activates pro-inflammatory and atherogenic signaling in endothelial cells via protein kinase C-beta (PKCbeta).
• PKCbeta is known to impair endothelial cell response to insulin.

Purpose of the Study:

• To investigate the hypothesis that apoCIII affects insulin signaling and function in vascular endothelial cells.
• To elucidate the role of apoCIII in endothelial dysfunction in vitro and in vivo.

Main Methods:

• Assessed insulin-induced tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1) in human umbilical vein endothelial cells (HUVECs).
• Measured phosphatidylinositol 3-kinase (PI3K)/Akt and endothelial nitric oxide synthase (eNOS) activation and nitric oxide (NO) release.
• Utilized protein kinase C-beta (PKCbeta) and MEK1 inhibitors.
• Evaluated effects in aorta from C57BL/6J mice and in HUVECs treated with apoCIII-rich very-low-density lipoprotein (VLDL).

Main Results:

• ApoCIII inhibited insulin-induced IRS-1 tyrosine phosphorylation and decreased PI3K/Akt activation in HUVECs.
• ApoCIII reduced eNOS activation and NO release, while activating PKCbeta and leading to IRS-1 serine phosphorylation.
• ApoCIII-rich VLDL and apoCIII impaired insulin signaling and endothelium-dependent relaxation in mouse aortas and HUVECs.
• Inhibition of PKCbeta or MEK1 restored impaired insulin signaling.

Conclusions:

• ApoCIII in VLDL impairs insulin-stimulated NO production and induces endothelial dysfunction.
• The adverse effects of apoCIII are mediated by PKCbeta activation, which inhibits the IRS-1/PI3K/Akt/eNOS pathway.
• ApoCIII serves as a key link between dyslipidemia and insulin resistance in endothelial cells, negatively impacting atheroprotective functions.