脂毒性和代谢健康的维持-猫眼课题宝

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

项目类别：

财政年份：

2023

资助国家：

美国

项目状态：

未结题

起止时间：

2023-07-01 至 2027-04-30

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

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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.

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