PDF(Pubmed)
Abstract：
Context-dependent physiological remodeling of the extracellular matrix (ECM) is essential for development and organ homeostasis. On the other hand, consumption of high-caloric diet leverages ECM remodeling to create pathological conditions that impede the functionality of different organs, including the heart. However, the mechanistic basis of high caloric diet-induced ECM remodeling has yet to be elucidated. Employing in vivo molecular genetic analyses in Drosophila, we demonstrate that high dietary sugar triggers ROS-independent activation of JNK signaling to promote fatty acid oxidation (FAO) in the pericardial cells (nephrocytes). An elevated level of FAO, in turn, induces histone acetylation-dependent transcriptional upregulation of the cytokine Unpaired 3 (Upd3). Release of pericardial Upd3 augments fat body-specific expression of the cardiac ECM protein Pericardin, leading to progressive cardiac fibrosis. Importantly, this pathway is quite distinct from the ROS-Ask1-JNK/p38 axis that regulates Upd3 expression under normal physiological conditions. Our results unravel an unknown physiological role of FAO in cytokine-dependent ECM remodeling, bearing implications in diabetic fibrosis.
摘要：
细胞外基质（ECM）的上下文依赖性生理重塑对于发育和器官稳态至关重要。另一方面,高热量饮食的消费利用ECM重塑来创造阻碍不同器官功能的病理条件，包括心脏。然而,高热量饮食诱导ECM重塑的机制基础尚未阐明。在果蝇中使用体内分子遗传分析，我们证明,饮食中高糖会触发非ROS依赖性的JNK信号激活,从而促进心包细胞(肾细胞)中的脂肪酸氧化(FAO).粮农组织的水平提高，反过来,诱导细胞因子未配对3（Upd3）的组蛋白乙酰化依赖性转录上调。心包Upd3的释放增加了心脏ECM蛋白Pericardin的脂肪体特异性表达，导致进行性心脏纤维化。重要的是,该途径与在正常生理条件下调节Upd3表达的ROS-Ask1-JNK/p38轴非常不同。我们的结果揭示了FAO在细胞因子依赖性ECM重塑中的未知生理作用，对糖尿病纤维化有影响。
