Apolipoproteins and Cell Adhesion Molecules - Adhesion Molecules - page 438

ApoC-III Impairs Insulin Stimulation of NO Production in
Vascular EC
ApoC-III directly activates pro-inl ammatory and atherogenic signaling in vascular
EC through PKCβ. Because PKCβ inhibits insulin action in endothelial cells and
apoC-III activates PKCβ in the same cells, Kawakami et al. then examined whether
apoC-III af ects insulin signaling in vascular EC ( Fig. 5 ) . h e results suggested
that apoC-III inhibited insulin-induced tyrosine phosphorylation of insulin
receptor substrate 1 (IRS-1), decreasing phosphatidylinositol 3-kinase (PI3K)/Akt
activation in human umbilical vein EC (HUVECs). h ese ef ects of apoC-III led to
reduced endothelial nitric oxide synthase (eNOS) activation and NO release into
the media. ApoC-III impaired insulin stimulation of NO production by vascular
endothelium and induced endothelial dysfunction in vivo . h is adverse ef ect of
apoC-III was mediated by its activation of PKCβ, which inhibits the IRS-1/PI3K/
Akt/eNOS pathway.
Fig. 5 Schema depicting the mechanisms by which apoC-III causes insulin resistance in vascular
endothelial cells. Insulin resistance in hepatocytes increases apoC-III production and secretion
into blood. ApoC-III in TG-rich lipoproteins in turn impairs insulin-induced NO production by
inhibiting IRS-1function in EC. h e inhibitory ef ects of apoC-III on NO production are likely to
be mediated by the activation of PKCβ and partly by ERK, which induce activation of IRS-1.