Non-remnant triglyceride-rich lipoproteins due to lipoprotein lipase deficiency increase atherosclerosis in mice

Although hypertriglyceridemia and postprandial lipemia associate with greater atherosclerosis, partially metabolized triglyceride-rich lipoproteins termed remnants rather than nascent lipoproteins have been implicated as the culprits. Whether chylomicrons are inherently atherogenic remains unclear. To test whether increased levels of nascent triglyceride-rich lipoproteins (TRLs) in the absence of markedly reduced LDL-C levels contribute 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 (Ldlrkd) 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-/-/Ldlrkd mice than control Ldlrkd mice. Aorta from hypertriglyceridemic mice had changes in the transcriptomes of endothelial cells, macrophages, and smooth muscle cells indicating vascular inflammation. Our data show that intact TRLs contribute to atherosclerosis, explain the association of postprandial lipemia and vascular disease, and prove that non-remnant TRLs are not benign. We induced LpL deficiency in LDL receptor knockout mice to assess the contribution of unhydrolyzed triglyceride-rich lipoproteins to atherosclerosis. LDLR KO mice with or without concomitant LpL deficiency were fed a western diet for 12 weeks, after which their aortic roots and brachiocephalic arteries were isolated for assessment of atherosclerotic lessions. In addition, we performed single cell RNA sequencing analysis of aortic arches from LDLR KO with or without concomitant LpL deficiency.