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 脂毒性是2型糖尿病并发症包括非酒精性脂肪肝的重要机制 非酒精性脂肪肝（NAFLD）。通过基因筛选，我们发现核仁小RNA（snoRNA）的丢失， 嵌入在核糖体蛋白L13 a（Rpl 13 a）基因座的内含子内赋予细胞对脂毒性的抗性 文化模式四种Rp 113 a snoRNA，SNORD 32A、SNORD 33、SNORD 34和SNORD 35 A，引导2 β-O- 新生18 S和28 S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。本研究将检验Rpl 13 a基因敲除 snoRNA在高脂饮食诱导的NAFLD小鼠模型中保护免受脂毒性组织损伤我们将定义 snoRNA丰度、mRNA翻译和膳食营养素暴露之间的机制联系。结果 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 并且具有鉴定用于治疗代谢性疾病的新的治疗靶点的潜力。