mTOR-Mediated Desaturation of Fatty Acids in Hepatic Insulin Resistance.

mTOR 介导的肝胰岛素抵抗中脂肪酸去饱和。

• 批准号: 10339318
• 负责人: Adam Salmon
• 金额: --
• 依托单位: SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10339318
• 关键词: Acyl Coenzyme A; Address; Affect; Animals; Automobile Driving; Biogenesis; Catabolism; Cell Culture Techniques; Cells; Coenzyme A; Complex; Data; Defect; Development; Diet; Diet Modification; Dietary Fats; Dietary Fatty Acid; Enzymes; Etiology; FRAP1 gene; Fatty Acids; Fatty acid glycerol esters; Functional disorder; Genetic; Goals; Health; Healthcare; Hepatic; Hepatocyte; Homeostasis; Impairment; Insulin; Insulin Resistance; Knockout Mice; Lead; Link; Liver; Liver Mitochondria; Mediating; Mediator of activation protein; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolic stress; Metabolism; Mitochondria; Morphology; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Nutritional; Outcome; Oxidoreductase; Pathology; Pathway interactions; Patients; Pharmacologic Substance; Play; Prevalence; Prevention; Primary carcinoma of the liver cells; Process; Regulation; Research; Risk; Role; Saturated Fatty Acids; Services; Signal Transduction; Source; Testing; Tissues; Unsaturated Fats; Unsaturated Fatty Acids; Veterans; Veterans Health Administration; Work; cost; dietary; fatty acid metabolism; fatty acid oxidation; flexibility; functional outcomes; genetic manipulation; glucose production; improved; insulin sensitivity; insulin signaling; lipid biosynthesis; lipid metabolism; member; mortality; mouse model; mutant mouse model; new therapeutic target; non-alcoholic fatty liver disease; novel; oxidation; pi bond; preference; prevent; response; saturated fat

Discharged members of the US Armed Services are at an increased risk of metabolic disease which is exemplified by the prevalence of type 2 diabetes mellitus (T2DM) affecting an estimated 1/3 of all VHA patients. A key defect in the etiology of T2DM is the inability of insulin to suppress hepatic glucose production, or hepatic insulin resistance. Alterations in hepatic lipid metabolism precede hepatic insulin resistance and are regulated largely by mitochondrial fatty acid oxidation (β-oxidation) and, in particular, the ability to maintain effective metabolic flexibility under different dietary states. Previous work has implicated mechanistic target of rapamycin (mTOR) as a mediator of this process through the regulation of β-oxidation. However, our preliminary work found an interesting dichotomy; inhibition of mTOR promotes β-oxidation of fatty acids when there is a prevalence of saturated fatty acids substrates available but in contrast impairs β-oxidation when unsaturated fatty acids are the primary dietary lipid sources. That is, unsaturated fatty acid catabolism by β- oxidation is not complete in the context of low mTOR singaling. β-oxidation of unsaturated fatty acids requires accessory enzymes to desaturate for use as mitochondrial substrates. Because the development of insulin resistance is linked to dysregulation in metabolic flexibility, we propose that mTOR-mediated regulation of this process is a key to maintaining hepatic insulin sensitivity and preventing metabolic disease. The long-term goal of this proposal is define a relationship that could be central to the development of hepatic insulin resistance. This metabolic dysfunction is highly prevalent among Veterans and is a significant long-term healthcare issue due to increased risk of developing additional pathologies associated with this condition, including non-alcoholic fatty liver disease and hepatocellular carcinoma. Treatment and prevention options will significantly reduce the health burden of Veteran patients as well as Veterans Health Administration costs associated with treatment. Our overall hypothesis is that mTOR regulates the response to dietary fatty acids through its regulation of β-oxidation accessory enzymes and that dysfunction in this pathway leads to hepatic insulin resistance. Our rationale for this study is that understanding how this pathway regulates nutrient usage under metabolic stress will serve as a means to define new therapeutic targets to be utilized for treatment and prevention of metabolic disease in Veterans. We test this hypothesis using both pharmaceutical and genetic manipulation of mTOR signaling and the rate limiting β-oxidation accessory enzyme 2,4 Dieonyl-CoA reductase (DECR1) in primary hepatocytes and mouse models in experimental aims that link this pathway with mitochondrial energetic function and metabolism. In aim 1, we test whether mTOR signaling has direct impact on the activity of DECR1 with a functional outcome on fat oxidation. In aim 2, we then test whether β-oxidation accessory enzymes in mice play a significant role in the development of hepatic insulin signaling under metabolic stress using a novel DECR1 knockout mouse model. In particular, we test the metabolic and mitochondrial response to metabolic stress from changing dietary sources of fat. In aim 3, we address remodeling of the hepatic mitochondria as a homeostatic mechanism to maintain metabolic flexibility and the potential role of β-oxidation accessory enzymes in this process. Hepatic insulin resistance is promoted by several factors including diet, genetics and liver pathology. By clarifying a central pathway in the process through mTOR and β-oxidation accessory enzymes, our approach will lead to breakthrough discoveries that will significantly enhance health research to help our Veterans.

退役的美国武装部队成员患代谢性疾病的风险增加 以2型糖尿病(T2 DM)的流行为例，据估计，影响所有VHA的三分之一 病人。2型糖尿病病因学上的一个关键缺陷是胰岛素无法抑制肝脏葡萄糖的产生， 或肝脏胰岛素抵抗。肝脂代谢的改变是肝脏胰岛素抵抗的先兆 主要受线粒体脂肪酸氧化(β-氧化)调节，特别是维持 不同饮食状态下的有效代谢灵活性。以前的工作已经牵涉到机械目标 雷帕霉素(MTor)作为这一过程的中介体，通过调节β的氧化作用。然而，我们的 初步工作发现了一个有趣的二分法；当mTOR被抑制时，促进脂肪酸的β氧化 饱和脂肪酸底物很普遍，但与之相反，当β氧化时 不饱和脂肪酸是主要的膳食脂肪来源。也就是说，不饱和脂肪酸分解代谢的β- 在低mTOR信令的情况下，氧化不完全。不饱和脂肪酸的β氧化需要 辅助酶去饱和度，用作线粒体底物。因为胰岛素的发展 耐药性与代谢灵活性的失调有关，我们认为mTOR介导的对此的调节 过程是维持肝脏胰岛素敏感性和预防代谢性疾病的关键。 这项提议长期目标是确定一种关系，这种关系可能是 肝脏胰岛素抵抗。这种代谢功能障碍在退伍军人中非常普遍，是一种显著的 由于发生与此相关的其他疾病的风险增加，导致长期医疗保健问题 病情，包括非酒精性脂肪性肝病和肝细胞癌。治疗和预防 选择方案将显著减轻退伍军人患者和退伍军人健康的健康负担 与治疗相关的管理费用。我们的总体假设是，mTOR调节对 膳食脂肪酸通过调节β氧化辅酶及其在这一途径中的功能障碍 导致肝脏胰岛素抵抗。我们进行这项研究的基本原理是，理解这条途径是如何 调节代谢应激下的营养使用将成为确定新的治疗目标的一种手段 用于治疗和预防退伍军人的代谢性疾病。 我们使用mTOR信号的药物和基因操作以及 原代肝细胞中限速型β氧化辅助酶2，4-二乙酰-辅酶A还原酶(DECR1. 小鼠模型的实验目的是将这一途径与线粒体能量功能和 新陈代谢。在目标1中，我们测试mTOR信号是否直接影响DECR1的活性 脂肪氧化的功能结果。在目标2中，我们随后测试了小鼠体内的β氧化辅酶 在代谢应激下肝脏胰岛素信号的发展中发挥重要作用 DECR1基因敲除小鼠模型。特别是，我们测试代谢和线粒体对新陈代谢的反应 改变脂肪的饮食来源所带来的压力。在目标3中，我们将肝脏线粒体的重构作为一种 维持代谢灵活性的动态平衡机制及β氧化辅助物的潜在作用 酶在这个过程中的作用。 肝脏胰岛素抵抗是由饮食、遗传和肝脏病理等多种因素促进的。通过 通过mTOR和β-氧化辅酶澄清这一过程中的中心途径，我们的方法 将导致突破性发现，将显著加强健康研究，以帮助我们的退伍军人。