Department of Human Genetics (S.S.D., A.K., S.R., S.H.T.L., M.A., P.P.), David Geffen School of Medicine at UCLA.
Obesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Finland (K.H.P.).
Arterioscler Thromb Vasc Biol. 2023 Oct;43(10):1788-1804. doi: 10.1161/ATVBAHA.123.319358. Epub 2023 Jul 6.
Adipocytes are crucial regulators of cardiovascular health. However, not much is known about gene expression profiles of adipocytes residing in nonfat cardiovascular tissues, their genetic regulation, and contribution to coronary artery disease. Here, we investigated whether and how the gene expression profiles of adipocytes in the subcutaneous adipose tissue differ from adipocytes residing in the heart.
We used single-nucleus RNA-sequencing data sets of subcutaneous adipose tissue and heart and performed in-depth analysis of tissue-resident adipocytes and their cell-cell interactions.
We first discovered tissue-specific features of tissue-resident adipocytes, identified functional pathways involved in their tissue specificity, and found genes with cell type-specific expression enrichment in tissue-resident adipocytes. By following up these results, we discovered the propanoate metabolism pathway as a novel distinct characteristic of the heart-resident adipocytes and found a significant enrichment of coronary artery disease genome-wide association study risk variants among the right atrium-specific adipocyte marker genes. Our cell-cell communication analysis identified 22 specific heart adipocyte-associated ligand-receptor pairs and signaling pathways, including THBS (thrombospondin) and EPHA (ephrin type-A), further supporting the distinct tissue-resident role of heart adipocytes. Our results also suggest chamber-level coordination of heart adipocyte expression profiles as we observed a consistently larger number of adipocyte-associated ligand-receptor interactions and functional pathways in the atriums than ventricles.
Overall, we introduce a new function and genetic link to coronary artery disease for the previously unexplored heart-resident adipocytes.
脂肪细胞是心血管健康的关键调节因子。然而，人们对驻留在非脂肪心血管组织中的脂肪细胞的基因表达谱、其遗传调控以及对冠状动脉疾病的贡献知之甚少。在这里，我们研究了皮下脂肪组织和心脏中脂肪细胞的基因表达谱是否存在差异，以及这种差异的程度如何。
我们使用了皮下脂肪组织和心脏的单细胞 RNA-seq 数据集，并对组织驻留脂肪细胞及其细胞间相互作用进行了深入分析。
我们首先发现了组织驻留脂肪细胞的组织特异性特征，确定了涉及它们组织特异性的功能途径，并找到了在组织驻留脂肪细胞中具有细胞类型特异性表达富集的基因。通过进一步研究这些结果，我们发现了丙酸盐代谢途径是心脏驻留脂肪细胞的一个新的独特特征，并发现了冠状动脉疾病全基因组关联研究风险变异在右心房特异性脂肪细胞标记基因中的显著富集。我们的细胞间通讯分析确定了 22 个特定的心脏脂肪细胞相关配体-受体对和信号通路，包括 THBS（血栓素）和 EPHA（ephrin 型-A），进一步支持了心脏脂肪细胞的独特组织驻留作用。我们的研究结果还表明，心脏脂肪细胞表达谱存在腔室水平的协调，因为我们观察到心房中的脂肪细胞相关配体-受体相互作用和功能途径的数量明显多于心室。
总的来说，我们为以前未被探索的心脏驻留脂肪细胞引入了一个新的功能和遗传与冠状动脉疾病的联系。
