Eruptive xanthoma model reveals endothelial cells internalize and metabolize chylomicrons, leading to extravascular triglyceride accumulation
Ainara G. Cabodevilla, … , Nada A. Abumrad, Ira J. Goldberg
Ainara G. Cabodevilla, … , Nada A. Abumrad, Ira J. Goldberg
Published June 15, 2021
Citation Information: J Clin Invest. 2021;131(12):e145800. https://doi.org/10.1172/JCI145800.
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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 2

EC BODIPY493/503–positive droplets become larger over time.

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EC BODIPY493/503–positive droplets become larger over time. (A–E) Aortas...
(A–E) Aortas obtained from fasted WT mice (A) or serum-deprived cultured MECs (B) were incubated with human chylomicrons (4 mg/dL TG in FBS-free medium) for 30 or 120 minutes. Analysis of BODIPY 493/503–positive puncta size (>1000 particles/group) showed a significant increase in particle size over time, with average size increasing more than 2-fold both ex vivo and in vitro (C). Data are represented as mean ± SEM of 4 (ex vivo) or 12 (in vitro) independent experiments. **P < 0.01; ****P < 0.0001, Student’s t test. (D and E) MECs were deprived of serum overnight to ensure LD depletion, then incubated with human chylomicrons (4 mg/dL TG) for the indicated times. (D) Average size of BODIPY 493/503–positive puncta after 30 minutes (~100 nm) or 120 minutes (~250 nm) exposure to chylomicrons. n = 12 independent experiments. ****P < 0.0001, Student’s t test. (E) Immunostaining for perilipin 2 (red). At 120 minutes, BODIPY 493/503–positive droplets (green) colocalized with perilipin 2 (lower panels, colocalization in yellow). There was no perilipin 2 signal or colocalization with BODIPY 493/503–positive droplets at shorter (30 minutes) incubations (upper panels). Scale bars: 5 μm. (F–H) Immunostaining for lipoprotein marker apoB. MECs incubated with chylomicrons for 30 or 120 minutes exhibited similar numbers of intracellular apoB-positive puncta (F). At 30-minute incubation, BODIPY 493/503–positive puncta (green) fully colocalized with apoB (magenta, G). Colocalization at 120 minutes was partial, with only smaller BODIPY 493/503–positive puncta colocalizing with apoB (H). White arrows indicate apoB/BODIPY 493/503–positive puncta. Scale bars: 10 μm. Additional inset magnification, ×2.5.