Control of lipid metabolism in insulin resistant states
胰岛素抵抗状态下脂质代谢的控制
基本信息
- 批准号:8297577
- 负责人:
- 金额:$ 37.85万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-05-19 至 2016-04-30
- 项目状态:已结题
- 来源:
- 关键词:ADD-1 proteinAcuteAdultAffectAntisense OligonucleotidesApolipoproteinsApolipoproteins BAtherosclerosisBiliaryBinding ProteinsCarbohydratesCellsCholelithiasisCholesterolChronicComplementComplexConsumptionDataDiabetes MellitusDietDietary CarbohydratesDiseaseDyslipidemiasEnzymesFatty LiverFatty acid glycerol estersFigs - dietaryFructoseGenesGenetic TranscriptionGoalsHepaticHepatocyteHomeostasisHyperglycemiaHypertriglyceridemiaIn VitroInsulinInsulin ReceptorInsulin ResistanceKnock-outKnockout MiceLeadLipidsLipoproteinsLiverMeasuresMediatingMessenger RNAMetabolicMetabolic syndromeModelingMorbidity - disease rateMusNutrientPhysiologyRegulationRegulatory ElementRoleSerumSignal PathwaySignal TransductionSirolimusSterolsTriglyceridesUnited StatesVery low density lipoproteinbaseeffective therapyfeedingin vivoinhibitor/antagonistinsightinsulin signalingknock-downlipid biosynthesislipid metabolismmicrosomal triglyceride transfer proteinmortalitymouse modelnutritionpreventreconstitutionresponsetranscription factor
项目摘要
DESCRIPTION (provided by applicant): The metabolic syndrome is a state of insulin resistance characterized by multiple derangements in lipid homeostasis, leading to dyslipidemia, atherosclerosis, hepatic steatosis, and cholesterol gallstones. The factors that drive these derangements are unknown but must be determined in order to effectively treat the metabolic syndrome. The transcription factors FoxO1 and Sterol Regulatory Element Binding Protein (SREBP)-1c are key regulators of insulin action. FoxO1 promotes transcription of the gluconeogenic enzymes, but also the enzymes necessary for VLDL secretion and biliary cholesterol secretion. SREBP-1c, on the other hand, induces the lipogenic enzymes. In normal livers, insulin suppresses FoxO1 and activates SREBP-1c. In the metabolic syndrome, insulin fails to suppress FoxO1 but SREBP-1c is paradoxically increased. This raises the question, what drives SREBP-1c in the presence of insulin resistance? Our preliminary data show that the livers of Liver Insulin Receptor Knockout (LIRKO) mice, which are unresponsive to insulin, show a rapamycin- sensitive increase in SREBP-1c in response to dietary carbohydrates. These data indicate the existence of an insulin-independent signaling pathway that could potentially allow the excessive consumption of carbohydrates to activate SREBP-1c and lipogenesis, even in the presence of insulin resistance. The overarching goal of this proposal is to identify the key driver of lipid metabolism in the insulin resistant state. We hypothesize that FoxO1, which fails to be suppressed by insulin, drives dyslipidemia, atherosclerosis and gallstones; but that SREBP-1c, induced by nutrients, drives lipogenesis and steatosis. Our aims are to (1) determine the extent to which FoxO1 and SREBP-1c promote atherosclerosis, steatosis, and cholesterol gallstones by knocking down FoxO1 or reconstituting SREBP-1c expression in the livers of LIRKO mice; and (2) to define the insulin-independent signaling pathways by which nutrients can activate SREBP-1c and lipogenesis. We expect to find that FoxO1 and SREBP-1c define two distinct metabolic signaling pathways that are both necessary for the full complement of derangements present in the metabolic syndrome.
PUBLIC HEALTH RELEVANCE: The metabolic syndrome affects approximately one third of adults in the United States. Much of the morbidity and mortality associated with this disorder can be ascribed to derangements in lipid homeostasis: dyslipidemia, atherosclerosis, cholesterol gallstones, and hepatic steatosis. The studies here will identify the key regulatory molecules that
drive these derangements, and ultimately lead to more rational and effective therapies for the metabolic syndrome.
描述(申请人提供):代谢综合征是一种胰岛素抵抗状态,其特征是多种脂类平衡紊乱,导致血脂紊乱、动脉粥样硬化、肝脏脂肪变性和胆固醇结石。导致这些紊乱的因素尚不清楚,但为了有效治疗代谢综合征,必须确定这些因素。转录因子FoxO1和甾醇调节元件结合蛋白(SREBP)-1c是胰岛素作用的关键调节因子。Foxo1促进糖异生酶的转录,也促进极低密度脂蛋白和胆汁胆固醇分泌所必需的酶的转录。另一方面,SREBP-1c诱导成脂酶。在正常肝脏中,胰岛素抑制FoxO1并激活SREBP-1c。在代谢综合征中,胰岛素不能抑制FoxO1,但SREBP-1c却矛盾地增加。这就提出了一个问题,在存在胰岛素抵抗的情况下,是什么驱动了SREBP-1c?我们的初步数据显示,肝脏胰岛素受体基因敲除(LIRKO)小鼠的肝脏对胰岛素没有反应,但对饮食中的碳水化合物反应,对雷帕霉素敏感的SREBP-1c增加。这些数据表明,存在胰岛素非依赖性的信号通路,即使在存在胰岛素抵抗的情况下,也可能允许过量摄入碳水化合物来激活SREBP-1c和脂肪生成。这项建议的首要目标是确定胰岛素抵抗状态下脂代谢的关键驱动因素。我们假设,未能被胰岛素抑制的FoxO1会导致血脂异常、动脉粥样硬化和胆结石;但营养诱导的SREBP-1c会导致脂肪生成和脂肪变性。我们的目标是(1)确定FoxO1和SREBP-1c通过下调FoxO1或重建SREBP-1c在LIRKO小鼠肝脏中的表达,在多大程度上促进动脉粥样硬化、脂肪变性和胆固醇结石;(2)确定营养物质激活SREBP-1c和脂肪生成的非胰岛素依赖的信号通路。我们期望发现FoxO1和SREBP-1c定义了两条不同的代谢信号通路,这两条通路都是代谢综合征中存在的全部紊乱所必需的。
公共卫生相关性:在美国,代谢综合征影响着大约三分之一的成年人。与这种疾病相关的大部分发病率和死亡率可归因于脂质平衡紊乱:血脂异常、动脉粥样硬化、胆固醇结石和肝脏脂肪变性。这里的研究将确定关键的调控分子,
驱使这些错乱,并最终导致更合理和有效的代谢综合征治疗。
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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Sudha B Biddinger其他文献
Sudha B Biddinger的其他文献
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Control of lipid metabolism in insulin resistant states
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