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 6

SR-BI deficiency reduces LD content in skin macrophages from iLpl–/– mice.

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SR-BI deficiency reduces LD content in skin macrophages from iLpl–/– mic...
(A) MECs treated with either control or SR-BI ASO were grown to confluency in Transwell inserts and deprived of FBS for 24 hours. On the day of the experiment, ECs were either left untreated (control) or exposed to a 30-minute pulse with chylomicrons, thoroughly washed, and incubated with FBS-free medium with or without atglistatin or BafA1. Inserts were then immediately placed into wells containing freshly harvested PMACs and cocultured for 4 hours. PMACs were immunostained for macrophage marker CD68 (red), and LDs were labeled with BODIPY493/503 (green). (B) Representative images of PMACs following coincubation with ECs treated as indicated. (C) LD/cell quantification. PMACs cocultured with ECs exposed to a chylomicron pulse exhibited significantly more LDs than those cocultured with untreated ECs. LD accumulation was significantly reduced in PMACs cocultured with ECs treated with BafA1 (but not atglistatin) following the chylomicron pulse. SR-BI–deficient ECs exposed to chylomicrons also failed to induce LD biogenesis in cocultured PMACs. Data are represented as mean ± SEM of 5 independent experiments. ****P < 0.0001, 1-way ANOVA. (D and E) iLpl–/– mice were injected with either control or SR-BI ASO. Skin samples from the backs of 6 mice per group, as well as 6 nonhypertriglyceridemic iLplfl/fl controls were immunostained for CD68 (red) and LD staining with BODIPY 493/503 (green). Samples were imaged by confocal microscopy (D), and the percentage of CD68/BODIPY 493/503–positive (yellow) macrophages was quantified (>4000 macrophages per group) (E). LpL deficiency significantly exacerbated LD accumulation in mouse skin macrophages as compared with floxed controls. This effect was significantly reduced in iLpl–/– mice treated with SR-BI ASO. Data are represented as mean ± SD. *P < 0.05; ****P < 0.0001 (significantly different from Lplfl/fl); ####P < 0.0001 (significantly different from iLpl–/–+ control ASO), 1-way ANOVA, Tukey’s multiple comparisons test. Scale bars: 10 μm.