Wellcome-MRC Institute of Metabolic Science and MRC Metabolic Diseases Unit, University of Cambridge, Cambridge, UK.
Cambridge University Nanjing Centre of Technology and Innovation, Nanjing, P. R. China.
Nat Metab. 2022 Apr;4(4):476-494. doi: 10.1038/s42255-022-00561-5. Epub 2022 Apr 25.
Resulting from impaired collagen turnover, fibrosis is a hallmark of adipose tissue (AT) dysfunction and obesity-associated insulin resistance (IR). Prolidase, also known as peptidase D (PEPD), plays a vital role in collagen turnover by degrading proline-containing dipeptides but its specific functional relevance in AT is unknown. Here we show that in human and mouse obesity, PEPD expression and activity decrease in AT, and PEPD is released into the systemic circulation, which promotes fibrosis and AT IR. Loss of the enzymatic function of PEPD by genetic ablation or pharmacological inhibition causes AT fibrosis in mice. In addition to its intracellular enzymatic role, secreted extracellular PEPD protein enhances macrophage and adipocyte fibro-inflammatory responses via EGFR signalling, thereby promoting AT fibrosis and IR. We further show that decreased prolidase activity is coupled with increased systemic levels of PEPD that act as a pathogenic trigger of AT fibrosis and IR. Thus, PEPD produced by macrophages might serve as a biomarker of AT fibro-inflammation and could represent a therapeutic target for AT fibrosis and obesity-associated IR and type 2 diabetes.
由于胶原蛋白代谢受损，纤维化是脂肪组织（AT）功能障碍和肥胖相关胰岛素抵抗（IR）的标志。脯肽酶，也称为肽酶 D（PEPD），通过降解脯氨酸二肽在胶原蛋白代谢中发挥重要作用，但它在 AT 中的具体功能相关性尚不清楚。在这里，我们表明在人和小鼠肥胖中，PEPD 在 AT 中的表达和活性降低，并且 PEPD 被释放到全身循环中，这促进了纤维化和 AT IR。通过基因敲除或药物抑制消除 PEPD 的酶功能会导致小鼠 AT 纤维化。除了其细胞内酶作用外，分泌的细胞外 PEPD 蛋白通过 EGFR 信号增强巨噬细胞和脂肪细胞的纤维炎症反应，从而促进 AT 纤维化和 IR。我们进一步表明，活性降低的脯肽酶活性与系统中升高的 PEPD 水平相关，PEPD 水平升高可作为 AT 纤维化和 IR 的致病触发因素。因此，巨噬细胞产生的 PEPD 可能作为 AT 纤维炎症的生物标志物，并可能成为 AT 纤维化和肥胖相关 IR 和 2 型糖尿病的治疗靶点。
