Eruptive xanthoma model reveals endothelial cells internalize and metabolize chylomicrons, leading to extravascular triglyceride accumulation
| Autor: | Ira J. Goldberg, Songtao Tang, Adam E. Mullick, Sungwoon Lee, Nada A. Abumrad, M. Mahmood Hussain, Ainara G. Cabodevilla, Jose O. Aleman, William C. Sessa |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine In vivo Lipid droplet Chylomicrons Human Umbilical Vein Endothelial Cells Xanthomatosis Animals Humans Aorta Triglycerides Gene knockdown Lipoprotein lipase Triglyceride Macrophages digestive oral and skin physiology Lipid Droplets General Medicine Metabolism Coculture Techniques Cell biology Endothelial stem cell Disease Models Animal Lipoprotein Lipase 030104 developmental biology chemistry 030220 oncology & carcinogenesis lipids (amino acids peptides and proteins) Research Article Chylomicron |
| Zdroj: | J Clin Invest |
| ISSN: | 1558-8238 |
| Popis: | Although tissue uptake of fatty acids from chylomicrons is primarily via lipoprotein lipase (LpL) hydrolysis of triglycerides (TGs), studies of patients with genetic LpL deficiency suggest additional pathways deliver dietary lipids to tissues. Despite an intact endothelial cell (EC) barrier, hyperchylomicronemic patients accumulate chylomicron-derived lipids within skin macrophages, leading to the clinical finding eruptive xanthomas. We explored whether an LpL-independent pathway exists for transfer of circulating lipids across the EC barrier. We found that LpL-deficient mice had a marked increase in aortic EC lipid droplets before and after a fat gavage. Cultured ECs internalized chylomicrons, which were hydrolyzed within lysosomes. The products of this hydrolysis fueled lipid droplet biogenesis in ECs and triggered lipid accumulation in cocultured macrophages. EC chylomicron uptake was inhibited by competition with HDL and knockdown of the scavenger receptor-BI (SR-BI). In vivo, SR-BI knockdown reduced TG accumulation in aortic ECs and skin macrophages of LpL-deficient mice. Thus, ECs internalize chylomicrons, metabolize them in lysosomes, and either store or release their lipids. This latter process may allow accumulation of TGs within skin macrophages and illustrates a pathway that might be responsible for creation of eruptive xanthomas. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|