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
基本信息
- 批准号:10211089
- 负责人:
- 金额:$ 32.89万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AcyltransferaseAdipose tissueAttenuatedAutomobile DrivingBioinformaticsCell CycleCellsColonColonic NeoplasmsDataDevelopmentDiagnosticDiseaseDisease OutcomeDisease ProgressionEpidemicEpithelialExhibitsFOXO3A geneFatty acid glycerol estersFeedbackGenetic TranscriptionGrowthHigh Fat DietHumanImmuneIndividualInflammationInflammation MediatorsInflammatoryInterleukin-10Intracellular Accumulation of LipidsInvestigationLinkLipaseLipidsLipolysisMediatingMediator of activation proteinMetabolicMetabolic PathwayMolecularMusMutationNormal tissue morphologyObese MiceObesityOrganellesOverweightPathway interactionsPatientsPharmacological TreatmentPharmacologyProcessRegulationSignal TransductionSolidThe Cancer Genome AtlasTherapeuticTissuesTranscriptTriglyceridesTumor stagebasecell growthcell transformationdiacylglycerol O-acyltransferaseeffective therapyinsightlipid biosynthesismembermouse modelnovelobese personpatient populationpreventprogenitortranscription factortranscriptometumortumorigenesistumorigenic
项目摘要
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.
摘要
肥胖的特征是全身脂肪堆积、炎症和不同疾病的肿瘤形成增强。
组织,包括结肠。肥胖时,细胞内的脂滴(LDs)在脂肪储存和非脂肪储存中积累
储存纸巾。与正常组织相比,这些细胞器在结肠肿瘤中增多,可能是
肥胖如何促进结肠肿瘤发生的解释。随着肥胖成为一种世界性的流行病,它是
比以往任何时候都更重要的是阐明LDS动力学(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
结肠肿瘤的发生,它将推动探索体内代谢重新编程的关键机制
肿瘤的发生对于制定有效的治疗方案是必要的。
我们用FOXO_3转录因子鉴定了LDS的一个自我加强的负调控环,包括
转录和代谢途径之间的信号转导,促进结肠炎症和
肿瘤发生学。在拟议的项目中,我们将调查如何通过以下方式加强这个监管网络
酰基转移酶1/2(DGATS)介导的脂肪生成促进肥胖的肿瘤发生。我们的初步数据
显示人类和小鼠结肠肿瘤的DGATS水平相对于正常水平升高(甚至更高
肥胖者和HFD肥胖小鼠的水平)。DGAT2转录本的升高与患者的生存不良有关。
DGATS水平的增加还通过脂肪甘油三酯脂肪酶(ATGL)促进LDS的利用。这个
肥胖和炎症介质诱导DGATS在结肠细胞中的表达并可能受到调控
通过Myc,在FOXO_3缺乏和HFD肥胖小鼠的结肠中也被激活。DGATS在人体内的抑制作用
结肠转化细胞阻断负责FOXO_3(PI3K)丢失的途径,降低LDS/ATGL,并
抑制细胞生长。我们假设升高的DGAT驱动LD和FOXO_3自增强环路,
它的阻断有效地关闭了这种新陈代谢、炎症和肿瘤形成的途径。确立这一点
新的发病机制将对结肠肿瘤的发生具有诊断和治疗意义。
由炎症性肥胖症驱动。拟议的项目将阐明DGATS介导的代谢机制
刺激结肠细胞生长(目标1),它将确定靶向DGATS在减重结肠中的影响
肿瘤发生(由HFD-肥胖症的突变和炎症驱动)及其相关的血管重构
免疫细胞格局(PMN,Mf),分子途径(Myc,PI3K)和转录组(Aim 2),它将
评估依赖DGAT的LD动力学在人类结肠肿瘤发生中的意义(高级,
与局部和TCGA患者(目标3)相关的炎性和肥胖相关肿瘤。
这些研究将为DGAT介导的转录和代谢提供关键的机制洞察
在结肠肿瘤发生中重新编程,为开发新的有效药物奠定坚实的平台
结肠炎、肿瘤形成和其他HFD相关疾病的药物治疗。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Suzana D. Savkovic其他文献
Enteropathogenic <em>E. coli</em> activates NF-kB, but does not increase paracellular permeability, by a calcium-independent/MAP kinase-dependent pathway
- DOI:
10.1016/s0016-5085(00)82488-9 - 发表时间:
2000-04-01 - 期刊:
- 影响因子:
- 作者:
Suzana D. Savkovic;Akila Ramaswamy;Athanasia Koutsouris;Gail Hecht - 通讯作者:
Gail Hecht
Su1257 EPIPLOIC ADIPOSE TISSUE (EPAT) IN OBESE INDIVIDUALS PROMOTES COLONIC TUMORIGENESIS: A NOVEL COLORECTAL MICROPHYSIOLOGICAL MODEL FOR STUDYING EPAT MEDIATED PROCESSIS IN COLONIC CELLS
- DOI:
10.1016/s0016-5085(23)02321-1 - 发表时间:
2023-05-01 - 期刊:
- 影响因子:
- 作者:
Patricia Snarski;Rida Iftikhar;Angelle King;Jenisha Ghimire;Emmanuelle Ruiz;Frank Lau;Suzana D. Savkovic - 通讯作者:
Suzana D. Savkovic
756 ELEVATED DIACYLGLYCEROL O-ACYLTRANSFERASES 1 AND 2 (DGAT1/2) REINFORCE A NEGATIVE REGULATORY LOOP OF LIPID DROPLETS AND FOXO3 TRANSCRIPTION FACTOR THAT DRIVES METABOLIC AND TUMEROGENIC REMODELING IN COLON CANCER FACILITATED BY OBESITY
- DOI:
10.1016/s0016-5085(23)01340-9 - 发表时间:
2023-05-01 - 期刊:
- 影响因子:
- 作者:
Jenisha Ghimire;Morgan E. Collins;Angelle King;Rida Iftikhar;Harrison M. Penrose;Patricia Snarski;Suzana D. Savkovic - 通讯作者:
Suzana D. Savkovic
45 TUMOR PROMOTING ROLE OF EPIPLOIC ADIPOSE TISSUE IN COLON OF OBESE INDIVIDUALS IS MEDIATED VIA LIPID DROPLETS ASSOCIATED ADIPOSE TRIGLYCERIDE LIPASE (ATGL)
- DOI:
10.1016/s0016-5085(24)00534-1 - 发表时间:
2024-05-18 - 期刊:
- 影响因子:
- 作者:
Patricia Snarski;Muhammad Naeem;Rida Iftikhar;Jenisha Ghimire;Suzana D. Savkovic - 通讯作者:
Suzana D. Savkovic
46 OBESITY-PROMOTED COLON CANCER PROGRESSION IS FACILITATED BY LIPID DROPLET-ASSOCIATED ADIPOSE TRIGLYCERIDE LIPASE (ATGL)
- DOI:
10.1016/s0016-5085(21)00783-6 - 发表时间:
2021-05-01 - 期刊:
- 影响因子:
- 作者:
Harrison M. Penrose;Morgan E. Collins;Rida Iftikhar;Suzana D. Savkovic - 通讯作者:
Suzana D. Savkovic
Suzana D. Savkovic的其他文献
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{{ truncateString('Suzana D. Savkovic', 18)}}的其他基金
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:
10863387 - 财政年份:2021
- 资助金额:
$ 32.89万 - 项目类别:
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 - 财政年份:2021
- 资助金额:
$ 32.89万 - 项目类别:
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:
10598554 - 财政年份:2021
- 资助金额:
$ 32.89万 - 项目类别:
Regulation of Lipid Droplets and FOXO3 in Intestinal Epithelial Cell Proliferatio
脂滴和FOXO3对肠上皮细胞增殖的调节
- 批准号:
8628084 - 财政年份:2014
- 资助金额:
$ 32.89万 - 项目类别:
Regulation of Lipid Droplets and FOXO3 in Intestinal Epithelial Cell Proliferatio
脂滴和FOXO3对肠上皮细胞增殖的调节
- 批准号:
8790510 - 财政年份:2014
- 资助金额:
$ 32.89万 - 项目类别:
Regulation of Lipid Droplets and FOXO3 in Intestinal Epithelial Cell Proliferatio
脂滴和FOXO3对肠上皮细胞增殖的调节
- 批准号:
8478067 - 财政年份:2012
- 资助金额:
$ 32.89万 - 项目类别:
Regulation of Lipid Droplets and FOXO3 in Intestinal Epithelial Cell Proliferatio
脂滴和FOXO3对肠上皮细胞增殖的调节
- 批准号:
8296895 - 财政年份:2012
- 资助金额:
$ 32.89万 - 项目类别:
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