Regulation of DGAT - dependent lipogenesis in colonic epithelial growth

摘要 肥胖的特征在于全身脂质积聚、炎症和不同组织中增强的肿瘤发生。 组织，包括结肠。随着肥胖，细胞内脂滴（LD）在脂肪储存和非脂肪储存中积累， 储存组织。相对于正常组织，这些细胞器在结肠肿瘤中增加，可能是结肠肿瘤中的细胞器之一。 解释肥胖如何促进结肠肿瘤的发生。随着肥胖症成为一种世界性的流行病， 比以往任何时候都更重要的是阐明由LDs动力学介导的肿瘤发生过程（脂肪生成和 脂肪分解）。这将为我们理解肥胖如何促进炎症提供概念上的进步 结肠肿瘤发生，它将推动探索代谢重编程的关键机制， 发展有效的治疗方案所必需的肿瘤发生。 我们确定了一个自我加强的负调控环的LD与FOXO 3转录因子，涉及 促进结肠炎症的转录和代谢途径之间的信号传导， 肿瘤发生在拟议的项目中，我们将研究如何通过以下方式加强这一监管网络： 酰基转移酶1/2（DGAT）介导的脂肪生成促进肥胖症中的肿瘤发生。我们的初步数据 显示DGAT水平在人类和小鼠结肠肿瘤中相对于正常升高（甚至更高 肥胖个体和HFD-肥胖小鼠中的水平）。DGAT2转录物升高与患者生存率低有关。 DGAT水平的这种增加还通过脂肪甘油三酯脂肪酶（ATGL）促进LD利用。的 DGAT的表达由肥胖和结肠细胞中的炎症介质诱导，并且可能受到调节 Myc也在FOXO 3缺陷和HFD肥胖小鼠的结肠中被激活。人中DGAT的抑制 结肠转化细胞阻断负责FOXO 3（PI3K）丢失的途径，降低LD/ATGL， 减弱细胞生长。我们假设升高的DGAT驱动LD和FOXO3自我强化循环， 其阻断有效地关闭了这种代谢性炎症和肿瘤发生途径。建立这个 这一新的机制对结肠肿瘤的发生，尤其是结肠癌的发生， 由炎症性肥胖症引起该项目将阐明DGATs介导的代谢机制 刺激结肠细胞生长（目的1），将鉴定靶向DGAT在减弱结肠癌中的作用。 肿瘤发生（由HFD肥胖症中的突变和炎症驱动）和相关的 免疫细胞景观（PMN，MF），分子途径（Myc，PI3K）和转录组（Aim 2），它将 评估DGAT依赖性LD动力学在人结肠肿瘤发生（晚期， 炎性和肥胖相关肿瘤）（目的3）。 这些调查将提供关键机制的见解DGAT介导的转录和代谢 结肠肿瘤发生中的重编程，并为开发新的有效的 用于结肠炎症、肿瘤发生和其它HFD相关病症的药理学治疗。

Abstract Obesity is characterized by systemic lipid accumulation, inflammation, and enhanced tumorigenesis in different tissues, including colon. With obesity, intracellular lipid droplets (LDs) are accumulated in fat storing and non-fat storing tissues. These organelles are increased in colonic tumors relative to normal tissues and may be one the explanation for how obesity facilitates colonic tumorigenesis. As obesity is becoming a worldwide epidemic, it is more important than ever to elucidate the tumorigenic processes mediated by LDs dynamics (lipogenesis and lipolysis). This will provide conceptual advances in our understanding of how obesity promotes inflammatory colonic tumorigenesis, and it will drive exploration of critical mechanisms of metabolic reprogramming within tumorigenesis necessary for the development of effective treatment options. We identified a self-reinforcing negative regulatory loop of LDs with the FOXO3 transcription factor involving signaling between transcriptional and metabolic pathways that facilitates colonic inflammation and tumorigenesis. In the proposed project, we will investigate how this regulatory network is reinforced through acyltransferases 1/2 (DGATs) mediated lipogenesis in facilitating tumorigenesis in obesity. Our preliminary data show that DGATs levels are elevated in human and mouse colonic tumors relative to normal (with even higher levels in obese individuals and HFD-obese mice). Elevated DGAT2 transcripts are linked to poor patient survival. This increase in DGATs levels also promotes LDs utilization through adipose triglyceride lipase (ATGL). The expression of DGATs is induced by obesity and inflammatory mediators in colonic cells and is possibly regulated by Myc that is also activated in the colon of FOXO3 deficient and HFD-obese mice. Inhibition of DGATs in human colonic transformed cells blocks the pathway responsible for loss of FOXO3 (PI3K), lowers LDs/ATGL, and attenuates cell growth. We hypothesize that elevated DGATs drive an LD and FOXO3 self-reinforcing loop, blockade of which effectively shuts down this metabolic inflammatory and tumorigenic pathway. Establishing this novel mechanism will have diagnostic and therapeutic significance in colonic tumorigenesis, especially those driven by inflammatory obesity. The proposed project will elucidate DGATs-mediated metabolic mechanisms stimulating colonic cell growth (Aim 1), it will identify the impact of targeting DGATs in attenuating colonic tumorigenesis (driven by mutation and inflammation in HFD-obesity) and the associated remodeling of the immune cell landscape (PMN, MF), molecular pathways (Myc, PI3K), and transcriptome (Aim 2), and it will assess the significance of the DGAT-dependent LD dynamics in human colonic tumorigenesis (advanced, inflammatory, and obesity-associated tumors) of local and TCGA patients (Aim 3). These investigations will provide key mechanistic insights into DGAT-mediated transcriptional and metabolic reprograming in colonic tumorigenesis and establish a solid platform for the development of novel effective pharmacological treatments for colonic inflammation, tumorigenesis, and other HFD-related disorders.