From the Inserm, UMR1048, Team 1, I2MC, Institute of Metabolic and Cardiovascular Diseases, Université de Toulouse, Toulouse, Cedex 4, France (A. Briot, P.D., F.V., C.B., A. Bouloumié)
From the Inserm, UMR1048, Team 1, I2MC, Institute of Metabolic and Cardiovascular Diseases, Université de Toulouse, Toulouse, Cedex 4, France (A. Briot, P.D., F.V., C.B., A. Bouloumié).
Arterioscler Thromb Vasc Biol. 2018 May;38(5):1134-1146. doi: 10.1161/ATVBAHA.118.310797. Epub 2018 Mar 15.
Adipose tissue (AT) dysfunction associated with obesity or aging is a major cause for lipid redistribution and the progression of cardiometabolic disorders. Our goal is to decipher the contribution of human AT microvascular endothelial cells (ECs) in the maintenance of fatty acid (FA) fluxes and the impact of senescence on their function.
We used freshly isolated primary microvascular ECs from human AT. Our data identified the endothelial FA handling machinery including FATPs (FA transport proteins) FATP1, FATP3, FATP4, and CD36 as well as FABP4 (FA binding protein 4). We showed that PPARγ (peroxisome proliferator-activated receptor gamma) regulates the expression of FATP1, CD36, and FABP4 and is a major regulator of FA uptake in human AT EC (hATEC). We provided evidence that endothelial PPARγ activity is modulated by senescence. Indeed, the positive regulation of FA transport by PPARγ agonist was abolished, whereas the emergence of an inflammatory response was favored in senescent hATEC. This was associated with the retention of nuclear FOXO1 (forkhead box protein O1), whereas nuclear PPARγ translocation was impaired.
These data support the notion that PPARγ is a key regulator of primary hATEC function including FA handling and inflammatory response. However, the outcome of PPARγ activation is modulated by senescence, a phenomenon that may impact the ability of hATEC to properly respond to and handle lipid fluxes. Finally, our work highlights the role of hATEC in the regulation of FA fluxes and reveals that dysfunction of these cells with accelerated aging is likely to participate to AT dysfunction and the redistribution of lipids.
与肥胖或衰老相关的脂肪组织（AT）功能障碍是脂质重新分布和心脏代谢疾病进展的主要原因。我们的目标是破译人类 AT 微血管内皮细胞（EC）在维持脂肪酸（FA）通量中的作用以及衰老对其功能的影响。
我们使用了从人脂肪组织中分离的新鲜原代微血管 EC。我们的数据确定了包括 FATPs（FA 转运蛋白）FATP1、FATP3、FATP4 和 CD36 以及 FABP4（FA 结合蛋白 4）在内的内皮 FA 处理机制。我们表明，PPARγ（过氧化物酶体增殖物激活受体 γ）调节 FATP1、CD36 和 FABP4 的表达，是人类 ATEC（hATEC）中 FA 摄取的主要调节剂。我们提供的证据表明，内皮细胞 PPARγ 活性受到衰老的调节。事实上，PPARγ 激动剂对 FA 转运的正向调节被消除，而衰老的 hATEC 中炎症反应的出现则受到青睐。这与 FOXO1（叉头框蛋白 O1）的核保留有关，而核 PPARγ 易位受损。
这些数据支持这样一种观点，即 PPARγ 是包括 FA 处理和炎症反应在内的原代 hATEC 功能的关键调节剂。然而，PPARγ 激活的结果受到衰老的调节，这种现象可能会影响 hATEC 适当响应和处理脂质通量的能力。最后，我们的工作强调了 hATEC 在 FA 通量调节中的作用，并揭示了这些细胞随着加速衰老而出现的功能障碍可能参与 AT 功能障碍和脂质再分布。
