Abstract
The effect of increased triglycerides (TGs) as an independent factor in atherosclerosis development has been contentious, in part, because severe hypertriglyceridemia associates with low levels of low-density lipoprotein cholesterol (LDL-C). To test whether hyperchylomicronemia, in the absence of markedly reduced LDL-C levels, contributes to atherosclerosis, we created mice with induced whole-body lipoprotein lipase (LpL) deficiency combined with LDL receptor (LDLR) deficiency. On an atherogenic Western-type diet (WD), male and female mice with induced global LpL deficiency (iLpl -/-) and LDLR knockdown (Ldlr kd ) developed hypertriglyceridemia and elevated cholesterol levels; all the increased cholesterol was in chylomicrons or large VLDL. After 12 weeks on a WD, atherosclerotic lesions both in the brachiocephalic artery and the aortic root were more severe in iLpl -/- /Ldlr kd mice compared to the control Ldlr kd mice. One likely mechanism for this is that exposure of the aorta to hyperchylomicronemia led to endothelial cell inflammation. Thus, our data show that intact chylomicrons contribute to atherosclerosis, explain the association of postprandial lipemia and vascular disease, and prove that hyperchylomicronemia is not benign.