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

基本信息

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
项目类别：
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

项目摘要

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.

修订后的摘要：胰岛素抵抗的发生是代谢综合征及其并发症的一个标志，肝脏与其他组织（脂肪和肌肉）一起也会产生胰岛素抵抗，从而导致高血糖和 II 型糖尿病的发生。尚不清楚；但神经酰胺（一种生物活性脂质代谢物）被认为是主要的罪魁祸首之一。针对神经酰胺从头合成途径的药物已显示出在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，而不是仅对神经酰胺产生影响，因为神经酰胺在肝细胞的代谢“健康”、其所处的亚细胞位置范围以及神经酰胺中发挥着不同的作用。由于其产生有多种代谢途径，因此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，但目前该提案中要测试的假设是一种称为中性的酶。鞘磷脂酶-2（nSMase-2，基因名称 smpd3）是通过鞘磷脂周转产生神经酰胺的四种不同酶之一，在调节肝细胞的胰岛素反应中发挥着独特的作用。这一假设得到了强有力的初步数据的支持。拟议的计划将确定细胞对胰岛素反应的这种新型信号轴的基本机制，目标 1 将破译 nSMase-2 对血浆的影响。体外细胞膜对神经酰胺稳态和胰岛素信号传导的影响目的 2 是测试体内 nSMase-2 与胰岛素抵抗之间的因果关系，并检查质膜上产生的神经酰胺对从头脂肪生成、脂质分泌和脂毒性的影响。最近开发的肝脏特异性基因敲除小鼠将用于这些研究。