Recent advances in understanding of how low-density lipoprotein (LDL) particles traverse the endothelial cell wall via receptor pathways are raising the possibility that similar mechanisms may also enable chylomicrons to enter the arterial wall. Extensive data presented by Professor Ira Goldberg, NYU Langone Health, New York, USA, suggest the need to look beyond current hypotheses on the atherogenicity of triglyceride-rich lipoproteins (TRL).
“Most fatty acids from triglycerides are released by lipoprotein lipase, and I don’t want to suggest anything different from that. But there is also a non-lipolysis pathway for lipid delivery via whole particles being taken up and processed in endothelial cells,” said Professor Goldberg.
He explained that traditional thinking has been that the LDL particle can penetrate the endothelial cell barrier because of its small size, while the much larger chylomicron cannot. However, in reality, LDL is too big to fit into tight junctions between endothelial cells, and research supports a role for SR-B1 and ALK1 receptors in endothelial transcytosis.1 For example, in an apoE knock-out mouse model also lacking endothelial SR-B1, LDL transcytosis was decreased, with an accompanying reduction in atherosclerosis.2
In recent experiments, Professor Goldberg and colleagues exposed endothelial cells to chylomicrons and measured gene expression. They found that all of the top 10 upregulated genes were involved in inflammation and atherosclerosis – suggesting that endothelial cells take on an inflammatory profile when exposed to chylomicrons.
“Nascent chylomicrons have often been viewed as non-atherogenic, but newer understanding of the uptake and transcytosis of plasma lipids across the endothelial cell barrier requires us to rethink this concept,” concluded Professor Goldberg.
- Zhang X, Sessa WC, Fernandez-Hernando C. Endothelial transcytosis of lipoproteins in atherosclerosis. Front Cardiovasc Med 2018; 5:130
- Huang L, Chambliss LK, Gao X et al. SR-B1 drives endothelial cell LDL transcytosis via DOCK4 to promote atherosclerosis. Nature 2019; 569: 565-569
Reportage by Jenny Bryan