Endothelial cell CD36 optimizes tissue fatty acid uptake
Ni-Huiping Son, … , Nada A. Abumrad, Ira J. Goldberg
Ni-Huiping Son, … , Nada A. Abumrad, Ira J. Goldberg
Published July 26, 2018
Citation Information: J Clin Invest. 2018;128(10):4329-4342. https://doi.org/10.1172/JCI99315.
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Research Article Endocrinology Metabolism

Endothelial cell CD36 optimizes tissue fatty acid uptake

Abstract

Movement of circulating fatty acids (FAs) to parenchymal cells requires their transfer across the endothelial cell (EC) barrier. The multiligand receptor cluster of differentiation 36 (CD36) facilitates tissue FA uptake and is expressed in ECs and parenchymal cells such as myocytes and adipocytes. Whether tissue uptake of FAs is dependent on EC or parenchymal cell CD36, or both, is unknown. Using a cell-specific deletion approach, we show that EC, but not parenchymal cell, CD36 deletion increased fasting plasma FAs and postprandial triglycerides. EC-Cd36–KO mice had reduced uptake of radiolabeled long-chain FAs into heart, skeletal muscle, and brown adipose tissue; these uptake studies were replicated using [11C]palmitate PET scans. High-fat diet–fed EC-CD36–deficient mice had improved glucose tolerance and insulin sensitivity. Both EC and cardiomyocyte (CM) deletion of CD36 reduced heart lipid droplet accumulation after fasting, but CM deletion did not affect heart glucose or FA uptake. Expression in the heart of several genes modulating glucose metabolism and insulin action increased with EC-CD36 deletion but decreased with CM deletion. In conclusion, EC CD36 acts as a gatekeeper for parenchymal cell FA uptake, with important downstream effects on glucose utilization and insulin action.

Authors

Ni-Huiping Son, Debapriya Basu, Dmitri Samovski, Terri A. Pietka, Vivek S. Peche, Florian Willecke, Xiang Fang, Shui-Qing Yu, Diego Scerbo, Hye Rim Chang, Fei Sun, Svetlana Bagdasarov, Konstantinos Drosatos, Steve T. Yeh, Adam E. Mullick, Kooresh I. Shoghi, Namrata Gumaste, KyeongJin Kim, Lesley-Ann Huggins, Tenzin Lhakhang, Nada A. Abumrad, Ira J. Goldberg

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Figure 3

EC-Cd36–/– mice have increased FFA and postprandial TG levels but improved glucose metabolism.

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EC-Cd36–/– mice have increased FFA and postprandial TG levels but improv...
(A) Plasma FFAs in 4-month-old male mice fasted for 16 hours (n = 6–8). (B) Plasma glucose levels (n = 6–7) in Cd36fl/fl, EC-Cd36–/–, and CM-Cd36–/– mice. (C) Postprandial TG response in Cd36fl/fl, EC-Cd36–/–, and CM-Cd36–/– mice. Plasma TG concentrations were measured 0, 2, 4, and 6 hours after intragastric administration of olive oil (n = 5–7). Also shown is the AUC for postprandial TG levels. (D) Four-month-old male mice (n = 4–8) were fasted for 16 hours before oral glucose administration. Tail blood was collected for glucose measurements at 0, 15, 30, 60, and 120 minutes after glucose administration. Also shown is the AUC of glucose excursions. (E) For ITTs, mice were fasted for 4 hours and given 0.75 U/kg BW insulin i.p. Tail blood samples were obtained before insulin administration (t0) and then 15, 30, 45, 60, and 120 minutes after insulin injection (n = 4–5 mice; data are representative of 2 independent experiments). Data represent the mean ± SD. *P < 0.05, #P < 0.01, and §P < 0.001 compared with Cd36fl/fl controls; 1-way ANOVA with Dunnett’s multiple comparisons test.