Lipotoxicity and Maintenance of Metabolic Health

脂毒性和代谢健康的维持

基本信息

批准号：
10753221
负责人：
JEAN E. SCHAFFER
金额：
$ 59.43万
依托单位：
JOSLIN DIABETES CENTER
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：
2023-07-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10753221
关键词：
Acceleration Adult Age Autophagocytosis Biogenesis Cell Culture Techniques Cell Death Cells Cholesterol Chronic Kidney Failure Complications of Diabetes Mellitus Data Diet Disease Enzymes Fatty Acids Fatty acid glycerol esters Fibrosis Fructose Functional disorder Genetic Screening Health Heart failure Hepatic Hepatocyte High Fat Diet Inflammation Introns Islets of Langerhans Knock-out Laboratories Link Lipids Liver Liver Cirrhosis Liver Dysfunction Liver Mitochondria Lysosomes Maintenance Mediator Messenger RNA Metabolic Metabolic Diseases Methylation Mitochondria Modeling Modification Molecular Mus Non-Insulin-Dependent Diabetes Mellitus Nonesterified Fatty Acids Nucleotides Nutrient Organ Oxidative Stress Oxidative Stress Induction Oxygen Consumption Palmitates RNA, Ribosomal, 28S Regulation Resistance Ribosomal Proteins Ribosomal RNA Ribosomes Site Small Nucleolar RNA Structure Testing Tissues Toxic effect Trans Fats Translational Regulation Triglycerides Untranslated RNA Up-Regulation Wild Type Mouse Work conditional knockout dietary endoplasmic reticulum stress genome-wide insight lipid metabolism loss of function mRNA Translation metabolic fitness mitochondrial fitness mitochondrial metabolism mouse model new therapeutic target non-alcoholic fatty liver disease novel novel therapeutics prevent response ribosome profiling trafficking translational potential

项目摘要

ABSTRACT Lipotoxicity is an important mechanism of complications in type 2 diabetes, including non-alcoholic fatty liver disease (NAFLD). Through a genetic screen, we discovered that loss of small nucleolar RNAs (snoRNAs) embedded within introns of the ribosomal protein L13a (Rpl13a) locus confers resistance to lipotoxicity in a cell culture model. The four Rpl13a snoRNAs, SNORD32A, SNORD33, SNORD34, and SNORD35A, guide 2¢-O- methyl nucleotide modifications at five sites on nascent 18S and 28S ribosomal RNAs that lie in close proximity to key functional centers of the ribosome structure. This study will test the hypothesis that knockout of Rpl13a snoRNAs protects from lipotoxic tissue damage in a mouse model of high fat diet-induced NAFLD. We will define the mechanistic links among snoRNA abundance, mRNA translation, and dietary nutrient exposures. Findings from this work will provide new insights into the pathophysiology of NAFLD and other diseases of lipid overload and have the potential to identify new therapeutic targets for treatment of metabolic diseases.

抽象的脂肪毒性是2型糖尿病并发症的重要机制，包括非酒精性脂肪肝疾病（NAFLD）。通过遗传筛查，我们发现小核仁RNA（SNORNA）的丧失嵌入核糖体蛋白L13A（RPL13A）基因座的内含子中，赋予细胞中对脂毒性的抗性文化模型。四个RPL13A SNORNAS，SNORD32A，SNORD33，SNORD34和SNORD35A，指南2¢-O-- 甲基核苷酸的修饰在近距离附近的新生18S和28S核糖体RNA上的五个位点到核糖体结构的关键功能中心。这项研究将检验RPL13A敲除的假设 SNORNA可保护高脂饮食诱导的NAFLD小鼠模型中的脂肪毒性组织损伤。我们将定义 SNORNA丰度，mRNA翻译和饮食营养素暴露之间的机械联系。发现这项工作将为NAFLD的病理生理和其他脂质超负荷的病理生理提供新的见解并有可能识别用于治疗代谢疾病的新治疗靶标。