Signaling and metabolic functions of nSMase-2 in hepatic steatosis and onset of insulin resistance

nSMase-2 在肝脂肪变性和胰岛素抵抗发作中的信号传导和代谢功能

• 批准号: 10735117
• 负责人: Mariana N Nikolova-Karakashian
• 金额: $ 54.25万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10735117
• 关键词: Address; Adipose tissue; Adverse effects; Affect; Animal Disease Models; Animal Model; Antibodies; Autophagocytosis; Biochemical Pathway; Biological; Cell membrane; Ceramides; Clinic; Data; Development; Diabetes Mellitus; Diet; Drug Targeting; Effectiveness; Enzymes; FOXO1A gene; Fatty Liver; Fatty acid glycerol esters; Gene Expression; Generations; Genes; Genetic; Gluconeogenesis; Health; Hepatic; Hepatocyte; Homeostasis; Human; Hydrophobicity; Hyperglycemia; Hyperinsulinism; In Vitro; Inflammation; Inflammatory; Insulin; Insulin Resistance; Knockout Mice; Link; Lipids; Liver; Location; Mediating; Metabolic; Metabolic Pathway; Metabolic syndrome; Metabolism; Molecular; Mus; Muscle; Names; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organelles; Palmitic Acids; Pathway interactions; Peripheral; Persons; Physiological; Play; Production; Protein phosphatase; Regulation; Research; Role; Signal Transduction; Site; Solid; Sphingolipids; Sphingomyelinase; Sphingomyelins; Testing; Tissues; Translations; clinically relevant; endoplasmic reticulum stress; experimental study; gain of function; in vivo; inhibitor; insulin regulation; insulin signaling; lipid biosynthesis; lipidomics; loss of function; mitochondrial dysfunction; mutant; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; obese patients; pharmacologic; preclinical study; prevent; protein kinase C zeta; public health relevance; response; saturated fat; sphingosine 1-phosphate

Revised ABSTRACT: The onset of insulin resistance is a hallmark of metabolic syndrome and its complications. Together with other tissues (the adipose and the muscle) liver also becomes insulin resistant, thus contributing to the onset of hyperglycemia and type II diabetes. The mechanisms of hepatic insulin resistance are not well understood; but ceramide, a bioactive lipid metabolite is considered one of the main culprits. Drugs targeting pathways for ceramide de novo synthesis have shown effectiveness in ameliorating aspects of metabolic syndrome in the mouse. These approaches however typically exert a very broad effect on all sphingolipids, both structural and bioactive, instead on ceramide alone. Due to the diverse roles that ceramide play in metabolic “health” of hepatocytes, the range of subcellular locations where it resides, and the variety of metabolic pathways for its generation, specific approaches to target distinct ceramide effects are needed for successful translation to the clinic, but are not available at the moment. The hypothesis to be tested in this proposal is that an enzyme called Neutral Sphingomyelinase-2 (nSMase-2, gene name smpd3), one of four distinct enzymes that can generates ceramide by the turnover of sphingomyelin, plays an unique role in the regulation of the insulin response of hepatocytes. This hypothesis is supported by strong preliminary data documenting its key aspects. The proposed plan will identify the underlying mechanisms of this novel signaling axis in cellular response to insulin. Aim 1 will decipher the impact of nSMase-2 at the plasma membrane on ceramide homeostasis and insulin signaling in vitro. Aim 2 is to test the cause-effect relationship between nSMase-2 and insulin resistance in vivo, and examine the impact of ceramide generated at the plasma membrane on de novo lipogenesis, lipid secretion, lipotoxicity and gluconeogenesis in vivo. A recently developed liver specific knockout mouse will be used in these studies.

修订摘要： 胰岛素抵抗的发生是代谢综合征及其并发症的标志。与其他组织（脂肪和肌肉）一起，肝脏也变得胰岛素抵抗，从而导致高血糖症和II型糖尿病的发作。肝脏胰岛素抵抗的机制尚不清楚，但神经酰胺，一种生物活性的脂质代谢产物被认为是主要的罪魁祸首之一。靶向神经酰胺从头合成途径的药物已显示出改善小鼠代谢综合征方面的有效性。然而，这些方法通常对所有鞘脂（结构和生物活性）产生非常广泛的影响，而不是单独对神经酰胺产生影响。 由于神经酰胺在肝细胞的代谢“健康”中发挥的不同作用，其所在的亚细胞位置的范围以及其产生的各种代谢途径，需要针对不同神经酰胺效应的特定方法才能成功转化为临床，但目前尚不可用。本提案中待检验的假设是，一种称为中性鞘磷脂酶-2（nSMase-2，基因名称smpd 3）的酶（可通过鞘磷脂周转产生神经酰胺的四种不同酶之一）在肝细胞胰岛素反应的调节中发挥独特作用。这一假设得到了记录其关键方面的强有力的初步数据的支持。该计划将确定这种新的信号轴在细胞对胰岛素的反应的潜在机制。目的1将在体外破译质膜上的nSMase-2对神经酰胺稳态和胰岛素信号传导的影响。目的2是在体内检测nSMase-2与胰岛素抵抗之间的因果关系，并检查在质膜上产生的神经酰胺对体内从头脂肪生成、脂质分泌、脂毒性和脂质生成的影响。最近开发的肝脏特异性基因敲除小鼠将用于这些研究。