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.

美国武装部队的出院成员的代谢疾病风险增加 用2型糖尿病（T2DM）的患病率示例，影响了所有VHA的估计1/3 患者。 T2DM病因的关键缺陷是胰岛素无法抑制肝葡萄糖的产生， 或肝胰岛素抵抗。肝脂质代谢的改变先于肝胰岛素耐药性，并且是 在很大程度上通过线粒体脂肪酸氧化（β-氧化）调节，尤其是维持的能力 在不同饮食状态下的有效代谢灵活性。以前的工作已经实施了机械目标 雷帕霉素（MTOR）通过调节β氧化而作为该过程的中介。但是，我们的 初步工作发现了一个有趣的二分法。 MTOR的抑制会促进脂肪酸的β-氧化 可用的饱和脂肪酸底物的流行率，但相反，当β-氧化损害时 不饱和脂肪酸是主要的饮食脂质来源。也就是说，β-不饱和脂肪酸分解代谢 在低MTOR唱片的背景下，氧化并不完整。不饱和脂肪酸的β氧化需要 辅助酶脱饱和以用作线粒体底物。因为胰岛素的发展 抗性与代谢柔韧性失调有关，我们提出MTOR介导的调节 过程是维持肝胰岛素敏感性和预防代谢疾病的关键。 该提案的长期目标是定义的，这可能是发展的关系 肝胰岛素抵抗。这种代谢功能障碍在退伍军人中非常普遍，这是一个重要的 长期医疗保健问题是由于增加与此相关的其他病理的风险增加而导致的 病情，包括非酒精性脂肪肝病和肝细胞癌。治疗和预防 选择将大大减少退伍军人患者以及退伍军人健康的健康烧伤 管理费用与治疗相关。我们的总体假设是MTOR调节对 饮食脂肪酸通过其调节β氧化辅助酶的调节和该途径中的功能障碍 导致肝胰岛素抵抗。我们对这项研究的理由是了解这种途径 在代谢压力下调节营养用法将是定义新的治疗靶标的手段 用于治疗和预防退伍军人的代谢疾病。 我们使用MTOR信号传导的药物和遗传操纵以及 限制β-氧化辅助酶2,4二酰氧蛋白（DEAP1）在原发性肝细胞中，并且 实验目标中的小鼠模型将此途径与线粒体能量函数联系起来 代谢。在AIM 1中，我们测试MTOR信号是否直接影响了降低的活性1 脂肪氧化的功能结果。在AIM 2中，我们测试小鼠中的β氧化辅助酶是否是 在代谢应激下使用新颖 降低1敲除鼠标模型。特别是，我们测试了代谢和线粒体对代谢的反应 脂肪来源不断变化的压力。在AIM 3中，我们将肝脏线粒体的重塑作为一个 保持代谢柔韧性和β氧化辅助的潜在作用的稳态机制 在此过程中的酶。 肝胰岛素抵抗是由多种因素促进的，包括饮食，遗传学和肝脏病理学。经过 通过MTOR和β氧化辅助酶在过程中阐明中心途径，我们的方法 将导致突破性发现，将大大增强健康研究以帮助我们的退伍军人。