Regulation of DGAT - dependent lipogenesis in colonic epithelial growth

结肠上皮生长中 DGAT 依赖性脂肪生成的调节

• 批准号: 10380792
• 负责人: Suzana D. Savkovic
• 金额: $ 32.23万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10380792
• 关键词: Acyltransferase; Adipose tissue; Attenuated; Automobile Driving; Bioinformatics; Cell Cycle; Cells; Colon; Colonic Neoplasms; Colonic inflammation; Data; Development; Diagnostic; Disease; Disease Outcome; Disease Progression; Epidemic; Epithelial; Exhibits; FOXO3A gene; Fatty acid glycerol esters; Feedback; Genetic Transcription; Growth; High Fat Diet; Human; Immune; Individual; Inflammation; Inflammation Mediators; Inflammatory; Interleukin-10; Intracellular Accumulation of Lipids; Investigation; Link; Lipase; Lipids; Lipolysis; Mediating; Mediator of activation protein; Metabolic; Metabolic Pathway; Molecular; Mus; Mutation; Normal tissue morphology; Obese Mice; Obesity; Organelles; Overweight; Pathway interactions; Patients; Pharmacological Treatment; Pharmacology; Process; Regulation; Signal Transduction; Solid; The Cancer Genome Atlas; Therapeutic; Tissues; Transcript; Triglycerides; Tumor stage; base; cell growth; cell transformation; colon growth; colon tumorigenesis; diacylglycerol O-acyltransferase; effective therapy; insight; lipid biosynthesis; member; mouse model; novel; obese person; patient population; prevent; progenitor; transcription factor; transcriptome; tumor; tumorigenesis; tumorigenic

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.

抽象的 肥胖的特点是全身脂质积累、炎症和不同部位肿瘤发生的增强。 组织，包括结肠。肥胖时，细胞内脂滴（LD）在脂肪储存和非脂肪中积累 储存组织。相对于正常组织，这些细胞器在结肠肿瘤中增多，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。随着肥胖正在成为一种全球流行病， 阐明 LD 动力学介导的致瘤过程（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展 结肠肿瘤发生，它将推动对结肠内代谢重编程关键机制的探索 肿瘤发生对于开发有效的治疗方案是必要的。 我们发现了 LD 的自我强化负调节环路，其中 FOXO3 转录因子涉及 转录和代谢途径之间的信号传导促进结肠炎症和 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) 介导脂肪生成，促进肥胖症的肿瘤发生。我们的初步数据 表明人类和小鼠结肠肿瘤中的 DGAT 水平相对于正常水平升高（甚至更高） 肥胖个体和 HFD 肥胖小鼠的水平）。 DGAT2 转录本升高与患者生存率较差有关。 DGAT 水平的增加还通过脂肪甘油三酯脂肪酶 (ATGL) 促进 LD 的利用。这 DGAT 的表达是由肥胖和结肠细胞中的炎症介质诱导的，并且可能受到调节 Myc 在 FOXO3 缺陷和 HFD 肥胖小鼠的结肠中也被激活。人体内 DGAT 的抑制 结肠转化细胞阻断导致 FOXO3 (PI3K) 丢失的途径，降低 LDs/ATGL，并 减弱细胞生长。我们假设 DGAT 升高会驱动 LD 和 FOXO3 自我强化循环， 阻断它可以有效地关闭这种代谢炎症和致瘤途径。建立这个 新机制对于结肠肿瘤的发生具有诊断和治疗意义，特别是那些 由炎症性肥胖驱动。拟议的项目将阐明 DGAT 介导的代谢机制 刺激结肠细胞生长（目标 1），它将确定靶向 DGAT 对减弱结肠细胞生长的影响 肿瘤发生（由 HFD 肥胖中的突变和炎症驱动）和相关的重塑 免疫细胞景观（PMN、MF）、分子通路（Myc、PI3K）和转录组（目标 2），它将 评估 DGAT 依赖性 LD 动态在人类结肠肿瘤发生中的重要性（高级， 局部和 TCGA 患者的炎症和肥胖相关肿瘤）（目标 3）。 这些研究将为 DGAT 介导的转录和代谢提供关键的机制见解 结肠肿瘤发生中的重编程并为开发新的有效药物建立坚实的平台 针对结肠炎症、肿瘤发生和其他 HFD 相关疾病的药物治疗。