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 October 8, 2018; First 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 1

CD36 distribution in human and mouse hearts and creation of EC- and CM-Cd36–/– mice.

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CD36 distribution in human and mouse hearts and creation of EC- and CM-C...
(A) CD36 antibody staining of CMs and blood vessel ECs from human and mouse hearts. Original magnification, ×20. (B) Male mouse heart suborgan fractionation showing Cd36 mRNA levels in different cell types (n = 12–18). Data represent mean ratios normalized to CM-Cd36–/– (set at 1.0). (C) Genomic structure of murine Cd36, the targeting vector, and the mutated allele. Gray boxes represent the numbered murine Cd36 exons. Red arrows indicate transcription orientation. Black bent arrows indicate the translation start site. PCR primers (blue arrows) were chosen to differentiate between the WT genomic allele and the homologously recombined allele. (D) PCR of tail genomic DNA (using primer 1) and (E) heart tissue DNA (using primer 2) from Cd36fl/fl, EC-Cd36–/–, and CM-Cd36–/– mice. (F) PCR product sequencing showing ablation of exons 3 and 4 of Cd36 gene after Cre-mediated recombination. (G) Heart Cd36 mRNA in EC-Cd36–/– and CM-Cd36–/– mice quantified by qRT-PCR using primer 3 (n = 5–6, mean ± SD). Data are corrected for 18S rRNA and normalized to Cd36fl/fl controls. Immunoblots show CD36 in EC-Cd36–/– and CM-Cd36–/– mouse hearts. (H) Immunoblots of CD36 in EC-Cd36–/– muscle, WAT, BAT, and liver. *P < 0.05, #P < 0.01 and §P < 0.001 compared with Cd36fl/fl controls; 1-way ANOVA with Dunnett’s multiple comparisons test.