Eruptive xanthoma model reveals endothelial cells internalize and metabolize chylomicrons, leading to extravascular triglyceride accumulation
Ainara G. Cabodevilla, Songtao Tang, Sungwoon Lee, Adam E. Mullick, Jose O. Aleman, M. Mahmood Hussain, William C. Sessa, Nada A. Abumrad, Ira J. Goldberg
Ainara G. Cabodevilla, Songtao Tang, Sungwoon Lee, Adam E. Mullick, Jose O. Aleman, M. Mahmood Hussain, William C. Sessa, Nada A. Abumrad, Ira J. Goldberg
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Research Article Endocrinology Metabolism

Eruptive xanthoma model reveals endothelial cells internalize and metabolize chylomicrons, leading to extravascular triglyceride accumulation

Abstract

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.

Authors

Ainara G. Cabodevilla, Songtao Tang, Sungwoon Lee, Adam E. Mullick, Jose O. Aleman, M. Mahmood Hussain, William C. Sessa, Nada A. Abumrad, Ira J. Goldberg

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Figure 4

Mechanisms of endothelial chylomicron uptake.

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Mechanisms of endothelial chylomicron uptake. (A) MEC were incubated for...
(A) MEC were incubated for 30 minutes with human chylomicrons in the absence (left panel) or presence of the endocytosis inhibitor dynasore (80 μM, right panel). Treatment with dynasore blocked chylomicron uptake, resulting in the accumulation of apoB/BODIPY 493/503–positive chylomicrons in the plasma membrane. Dashed lines show the outline of the cell. (B–E) Cultured ECs were deprived of serum overnight, and DiI-labeled human chylomicrons (4 mg/dL TG, red) were used to monitor uptake after a 30-minute pulse. (B) Coincubation with apoB18 peptide (the NH2-terminal sequence of apoB100, 0.4 or 0.8mg/dL) significantly inhibited DiI-chylomicron uptake in MECs. Data are represented as mean ± SD of 8 independent experiments. All comparisons are with control. *P < 0.05; ***P < 0.001, 1-way ANOVA, Dunnet’s multiple comparisons test. (C) Cells treated with control siRNA or ALK1 siRNA were deprived of serum overnight and pulsed for 30 minutes with DiI-labeled chylomicrons. DiI-chylomicron uptake was not significantly reduced in ALK1-deficient cells. (D) DiI-chylomicron uptake was significantly inhibited by coincubation with unlabeled HDL (25 mg/dL cholesterol). (E) MECs were treated with either control or SR-BI ASO for 24 hours, deprived of serum overnight, and pulsed with DiI-chylomicron. Knockdown of SR-BI significantly inhibited DiI-chylomicron uptake. Data are represented as mean ± SEM of 4–9 independent experiments. All comparisons are with control. *P < 0.05; ****P < 0.0001, Student’s t test. Scale bars: 10 μm. Additional inset magnification, ×2.