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 5

SR-BI deficiency inhibits in vivo aortic EC CM uptake and LD accumulation.

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SR-BI deficiency inhibits in vivo aortic EC CM uptake and LD accumulatio...
WT, iLplfl/fl, and iLpl–/– mice (6–8 per group) were injected with either control or SR-BI ASO (100 mg/kg) once a week for 3 weeks. Loss of SR-BI expression was monitored by RT-PCR of liver (A) and aorta (B) as well as by immunostaining of aortic EC with SR-BI (D, green; quantified in C). **P < 0.01, Student’s t test. (E–G) DiI-CM (0.5 mg/g TG) was administered retroorbitally to WT mice 72 hours after the last ASO injection. Mice were sacrificed and their aortas harvested 15 minutes after DiI-CM administration, and DiI-CM within aortic ECs were visualized by confocal microscope. Treatment with SR-BI ASO induced fasting hypertriglyceridemia (E), and circulating TG levels were significantly elevated 15 minutes after DiI-CM injection as compared with mice treated with control ASO (F). SR-BI knockdown significantly inhibited DiI-CM uptake in aortic ECs (F, DiI-CM shown in red). White arrows indicate DiI-CM. All comparisons are with control ASO. **P < 0.01; ****P < 0.0001, Student’s t test. (H–K) Seventy-two hours after the last ASO injection (H), iLplfl/fl and iLpl–/– mice were fasted overnight and given olive oil by oral gavage (10 ml/kg). Circulating plasma TG levels (I) and aortic EC LD content (J) were assessed 180 minutes after gavage. As expected, iLpl–/– mice treated with control ASO exhibited a significant increase in LD accumulation (K, middle panel) as compared with floxed controls (K, left panel). This phenotype was rescued by SR-BI downregulation (K, right panel). Data are represented as mean ± SD. ***P < 0.001; ****P < 0.0001, 1-way ANOVA, Dunnet’s multiple comparisons test. Scale bars: 10 μm.