Control of lipid metabolism in insulin resistant states

胰岛素抵抗状态下脂质代谢的控制

• 批准号: 8297577
• 负责人: Sudha B Biddinger
• 金额: $ 37.85万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/8297577
• 关键词: ADD-1 protein; Acute; Adult; Affect; Antisense Oligonucleotides; Apolipoproteins; Apolipoproteins B; Atherosclerosis; Biliary; Binding Proteins; Carbohydrates; Cells; Cholelithiasis; Cholesterol; Chronic; Complement; Complex; Consumption; Data; Diabetes Mellitus; Diet; Dietary Carbohydrates; Disease; Dyslipidemias; Enzymes; Fatty Liver; Fatty acid glycerol esters; Figs - dietary; Fructose; Genes; Genetic Transcription; Goals; Hepatic; Hepatocyte; Homeostasis; Hyperglycemia; Hypertriglyceridemia; In Vitro; Insulin; Insulin Receptor; Insulin Resistance; Knock-out; Knockout Mice; Lead; Lipids; Lipoproteins; Liver; Measures; Mediating; Messenger RNA; Metabolic; Metabolic syndrome; Modeling; Morbidity - disease rate; Mus; Nutrient; Physiology; Regulation; Regulatory Element; Role; Serum; Signal Pathway; Signal Transduction; Sirolimus; Sterols; Triglycerides; United States; Very low density lipoprotein; base; effective therapy; feeding; in vivo; inhibitor/antagonist; insight; insulin signaling; knock-down; lipid biosynthesis; lipid metabolism; microsomal triglyceride transfer protein; mortality; mouse model; nutrition; prevent; reconstitution; response; transcription factor

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（由申请人提供）：代谢综合征是一种胰岛素抵抗状态，其特征是脂质稳态中多种危险，导致血脂异常，动脉粥样硬化，动脉粥样硬化，肝脂肪变性和胆固醇胆结石。驱动这些危险的因素尚不清楚，但必须确定才能有效治疗代谢综合征。转录因子FOXO1和固醇调节元件结合蛋白（SREBP）-1c是胰岛素作用的关键调节剂。 FOXO1促进了糖原性酶的转录，还促进了VLDL分泌和胆固醇分泌所需的酶。另一方面，SREBP-1C诱导脂肪酶。在正常肝脏中，胰岛素抑制FOXO1并激活SREBP-1C。在代谢综合征中，胰岛素无法抑制FOXO1，但SREBP-1C自相矛盾地增加。这就提出了一个问题，是什么在存在胰岛素抵抗的情况下驱动SREBP-1C？我们的初步数据表明，肝胰岛素受体敲除（LIRKO）小鼠的肝脏对胰岛素无反应，显示出雷帕霉素对SREBP-1C的敏感性增加，以响应饮食中的碳水化合物。这些数据表明存在非胰岛素非依赖性信号通路，即使在存在胰岛素耐药的情况下，碳水化合物的过量消耗也会激活SREBP-1C和脂肪形成。该提案的总体目标是确定抗胰岛素耐药性状态下脂质代谢的关键驱动力。我们假设胰岛素无法抑制FOXO1驱动血脂异常，动脉粥样硬化和胆结石。但是，由养分引起的SREBP-1C驱动脂肪生成和脂肪变性。我们的目的是（1）确定FOXO1和SREBP-1C在多大程度上促进动脉粥样硬化，脂肪变性和胆固醇胆结石，通过击倒FOXO1或重新构建Lirko小鼠肝中的SREBP-1C表达。 （2）定义胰岛素非依赖性信号通路，养分可以激活SREBP-1C和脂肪生成。我们希望发现FOXO1和SREBP-1C定义了两种不同的代谢信号通路，这都是代谢综合征中存在的危险的完全补充所必需的。 公共卫生相关性：代谢综合征影响美国大约三分之一的成年人。与这种疾病相关的许多发病率和死亡率可能归因于脂质稳态中的扰动：血脂异常，动脉粥样硬化，胆固醇胆结石和肝脂肪变性。这里的研究将确定关键的调节分子 驱动这些危险，并最终导致代谢综合征的更合理和有效的疗法。