Lipotoxicity and Maintenance of Metabolic Health

脂毒性和代谢健康的维持

• 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
• 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

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.

摘要 脂肪毒性是包括非酒精性脂肪肝在内的2型糖尿病并发症的一个重要机制 疾病(NAFLD)。通过基因筛查，我们发现小核仁RNA(SnoRNAs)的丢失 嵌入核糖体蛋白L13a(Rpl13a)基因座内含子使细胞对脂毒性产生抵抗 文化模式。四个RPL13a snoRNA，SNORD32A、SNORD33、SNORD34和SNORD35A，指南2？O- 新生的18S和28S核糖体RNA上5个位点的甲基核苷酸修饰 核糖体结构的关键功能中心。这项研究将检验Rpl13a基因敲除的假设 在高脂饮食诱导的NAFLD小鼠模型中，snoRNAs保护脂肪毒性组织损伤。我们将定义 SnoRNA丰度、信使核糖核酸翻译和膳食营养暴露之间的机制联系。发现 这项工作将为NAFLD和其他脂质过载疾病的病理生理学提供新的见解 并有可能为治疗代谢性疾病确定新的治疗靶点。