Abstract：
Intestinal fibrosis is a common complication of Crohn\'s disease and characterized by excessive extracellular matrix (ECM) deposition. The aryl hydrocarbon receptor (AhR) detects micronutrients and microbial metabolites in diet and can attenuate intestinal fibrosis with unclear mechanisms. In this study, AhR activation was demonstrated to downregulate the transcription of collagen I and fibronectin in a Sp1- but not Sp3- or AP-1-dependent manner. A suppressed fatty acid synthesis was highlighted using untargeted metabolomics analyses, and synthetic products, palmitic acid (PA), were used as the intermediary agent. After a screening study, fatty acid synthase (FASN) was identified as the main targeted protein, and AhR activation regulated \"HDAC3-acetylation\" signals but not glycosylation to enhance FASN degradation. Furthermore, results of bioinformatics analysis and others showed that after being activated, AhR targeted miR-193a-3p to control HDAC3 transcription. Collectively, AhR activation inhibited ECM deposition and alleviated intestinal fibrosis by limiting fatty acid synthesis subsequent to the inhibition of \"miR-193a-3p-HDAC3-FASN\" signals.
摘要：
肠纤维化是克罗恩病的常见并发症,其特征是细胞外基质(ECM)沉积过多。芳香烃受体（AhR）可检测饮食中的微量营养素和微生物代谢产物，并可在不清楚的机制下减轻肠纤维化。在这项研究中,AhR激活被证明以Sp1-而不是Sp3-或AP-1依赖性方式下调胶原蛋白I和纤连蛋白的转录。使用非靶向代谢组学分析突出了抑制的脂肪酸合成，和合成产品，棕榈酸(PA),被用作中介。经过筛选研究,脂肪酸合成酶（FASN）被确定为主要的靶向蛋白，和AhR激活调节“HDAC3-乙酰化”信号但不糖基化以增强FASN降解。此外，生物信息学分析等结果表明，被激活后，AhR靶向miR-193a-3p以控制HDAC3转录。总的来说，AhR激活通过在抑制“miR-193a-3p-HDAC3-FASN”信号后限制脂肪酸合成来抑制ECM沉积并减轻肠纤维化。
