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 1

Mouse aortic ECs accumulate LDs after an olive oil gavage in the absence of LpL or endothelial CD36.

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Mouse aortic ECs accumulate LDs after an olive oil gavage in the absence...
Three- to four-month-old male iLplfl/fl, iLpl–/–, EC-Cd36fl/fl, and EC-Cd36–/– mice were fasted for 16 hours and given olive oil by oral gavage (10 ml/kg). Plasma TG and aortic EC LD content were assessed at the indicated times (n = 5–8 mice/group/time point). (A–C) Both iLplfl/fl and iLpl–/– mice exhibited BODIPY 493/503–positive (green) LDs within aortic ECs, as visualized by confocal microscopy imaging of V-cadherin–immunostained (red) samples (A). Unlike floxed controls, iLpl–/– mice exhibited LDs within aortic ECs prior to the olive oil gavage (A, left panels). In the absence of LpL lipolysis, plasma TG (B) and LD accumulation (C) were significantly increased. (D–F) EC-specific CD36 deletion resulted in an increase in aortic EC LD content (D, quantified in F), which was mirrored by elevated plasma TG levels (E). All comparisons are with flox/flox controls. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001, 2-way ANOVA. (G–M) MECs were deprived of serum overnight to ensure LD depletion (G) and pretreated with LpL (10 U/ml) (I) or LpL+ heparin (10 U/ml). (J) or maintained in FBS-free medium (H) for 1 hour before a 120-minute incubation with human chylomicrons. Samples were immunostained with LD marker perilipin 2 (red) and stained with BODIPY 493/503 (green). LDs were significantly larger in the presence of LpL+/– heparin pretreatment (K), and their size correlated with the presence of FFAs in the media after treatment (M), which was significantly increased in samples pretreated with LpL+/– heparin (L). Data are represented as mean ± SEM of 7 independent experiments. **P < 0.01; ***P < 0.001; ****P < 0.0001, 1-way ANOVA, Dunnet’s multiple comparisons test. Scale bars: 10 μm. Additional inset magnification, ×2.5.