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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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 3

Intracellular chylomicron hydrolysis at the lysosomal compartment precedes LD biogenesis in ECs.

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Intracellular chylomicron hydrolysis at the lysosomal compartment preced...
(A–E) Cultured MECs were deprived of serum overnight and exposed to human chylomicrons (4 mg/dL in FBS-free medium). After a 30-minute pulse, cells were either fixed (0 minutes) or maintained in FBS-free medium for 120 minutes. (A) As expected, cells fixed immediately after the chylomicron pulse exhibited intracellular apoB/BODIPY 493/503–positive puncta (average size, ~100 nm, E). (B) Incubation for 120 minutes in FBS-free medium after pulse resulted in loss of intracellular apoB signal (quantified in C), accompanied by the appearance of larger, BODIPY 493/503–positive puncta (average size ~ 300 nm, E). Data are represented as mean ± SEM of 8 independent experiments. ****P < 0.0001, Student’s t test. (F–I) MECs were pulsed for 30 minutes with human chylomicrons, then fixed (F) or switched for 120 minutes to FBS-free medium alone (G) or in the presence of ATGL inhibitor atglistatin (H) or lysosomal proton pump inhibitor BafA1. (I). Average BODIPY 493/503–positive particle size (n = 7 independent experiments) is represented in J. Inhibition of ATGL did not preclude chylomicron degradation as monitored by loss of intracellular apoB signal nor the appearance of large (~300 nm) LDs. Conversely, inhibition of lysosomal hydrolysis with BafA1 resulted in the retention of apoB/BODIPY 493/503–positivecytoplasmic puncta (~100 nm) for the duration of the treatment. Data are represented as mean ± SD. ***P < 0.001; ****P < 0.0001, 1-way ANOVA, Dunnet’s multiple comparisons test. Scale bars: 10 μm. Additional inset magnification, ×2.