Role of Ceramide in Hepatic Insulin Resistance

神经酰胺在肝胰岛素抵抗中的作用

• 批准号: 7565069
• 负责人: SCOTT A SUMMERS
• 金额: $ 18.77万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-15 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7565069
• 关键词: Adipocytes; Adipose tissue; Affect; Anabolism; Animal Model; Animals; Atherosclerosis; Biological Models; Blood Circulation; Cardiovascular Diseases; Ceramides; Chronic; Condition; Consensus; Coupled; Cultured Cells; Data; Diabetes Mellitus; Diet; Dose; Elevation; Enzymes; Event; Famines; Fatty Acids; Genetic; Glucocorticoids; Glucose; Glycolysis; Hepatic; Hepatocyte; Hormones; Hydrolysis; In Vitro; Inflammation; Inflammatory; Insulin; Insulin Resistance; Intestines; Investigation; Link; Liver; Locales; Malignant Neoplasms; Manuscripts; Mediating; Metabolic stress; Metabolic syndrome; Molecular; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Nutrient; Obesity; Pathway interactions; Peripheral; Phenotype; Phosphotransferases; Physiological; Principal Investigator; Production; Protein Isoforms; Protein Phosphatase 2A Regulatory Subunit PR53; Publishing; Rate; Regulation; Risk Factors; Rodent; Role; Rosa; SET gene; Saturated Fatty Acids; Serum; Signal Transduction; Skeletal Muscle; Skeletal system; Sphingolipids; Sphingomyelins; Stimulus; Stress; Testing; Time; Tissues; Translating; Tumor Necrosis Factor-alpha; Up-Regulation; Visceral; abstracting; acute stress; base; blood glucose regulation; cytokine; dihydroceramide desaturase; enzyme activity; glucose tolerance; hypertensive heart disease; in vivo; in vivo Model; inhibitor/antagonist; insulin sensitivity; interest; mixed lineage kinase 3; novel; peptide hormone; programs; response; saturated fat; stress-activated protein kinase 1; uptake

The peptide hormone insulin stimulates the uptake and storage of glucose and other nutrients into adipose tissue and skeletal muscle while simultaneously repressing glucose efflux from the liver. Insulin resistance occurs when a normal dose of the hormone is incapable of eliciting these anabolic responses, and the condition is a risk factor for cardiovascular disease, type 2 diabetes, and certain forms of cancer. Pathogenic factors implicated in the onset of insulin resistance (e.g. saturated fatty acids, tumor necrosis factor-alpha, and glucocorticoids) have been shown to selectively induce the synthesis of ceramide, a sphingolipid that has been shown to antagonize insulin action. We present findings indicating that the inhibition of ceramide synthesis in rodents ameliorates insulin resistance caused by saturated fats, glucocorticoids, and obesity. Moreover, we include preliminary data identifying the liver as a likely target of ceramide action, that white adipocytes secrete ceramide, and that ceramide levels within the portal circulation are markedly elevated during times of metabolic stress. Because of these data, we hypothesize that ceramide generated in and secreted from visceral adipose tissue modulates insulin sensitivity and glucose homeostasis in the liver as a physiological mechanism for communicating nutrient status or energy need. To test the role of this enterohepatic axis in the regulation of peripheral insulin sensitivity, we will complete the following aims: first, we will identify the primary tissues that produce the pools of ceramide which impaig glucose tolerance; second, we will investigate the role of factors implcated in insulin resistance (e.g. tumor necrosis factor-alpha, glucocorticoids) in the modulation of ceramide synthesis; and third, we will elucidate the mechanism underyling ceramide's induction of hepatic insulin resistance. Collectively, these studies could uncover a novel regulatory axis that modulates peripheral insulin sensitivity and energy utilization during times of feast, famine, or stress.

肽激素胰岛素刺激葡萄糖和其他物质的摄取和储存， 同时抑制葡萄糖从肝脏流出。 当正常剂量的激素不能引起这些合成代谢时，就会发生胰岛素抵抗。 反应，并且该疾病是心血管疾病、2型糖尿病和某些形式的糖尿病的危险因素 癌与胰岛素抵抗发病有关的致病因素（如饱和脂肪酸、肿瘤 坏死因子-α和糖皮质激素）已经显示出选择性地诱导神经酰胺的合成， 已显示拮抗胰岛素作用鞘脂。我们目前的调查结果表明， 抑制啮齿类动物中的神经酰胺合成可改善由饱和脂肪引起的胰岛素抗性， 糖皮质激素和肥胖。此外，我们包括初步数据，确定肝脏作为一个可能的目标， 神经酰胺作用，白色脂肪细胞分泌神经酰胺，门脉循环内的神经酰胺水平 在代谢应激时会显著升高基于这些数据，我们假设神经酰胺 内脏脂肪组织产生和分泌的胰岛素调节胰岛素敏感性和葡萄糖稳态 在肝脏中作为一种生理机制，用于传达营养状态或能量需求。测试的作用 这一肝肠轴在调节外周胰岛素敏感性方面，我们将完成以下目的： 首先，我们将确定产生神经酰胺池的主要组织，这些神经酰胺池会影响葡萄糖耐量; 第二，我们将研究与胰岛素抵抗有关的因子（例如肿瘤坏死因子-α， 糖皮质激素）在神经酰胺合成的调制;第三，我们将阐明的机制， 神经酰胺诱导肝脏胰岛素抵抗。总的来说，这些研究可以揭示一种新的监管机制， 在饱餐、饥饿或压力期间调节外周胰岛素敏感性和能量利用的轴。