Inflammation and hepatic lipid metabolism

炎症与肝脏脂质代谢

基本信息

批准号：
10187564
负责人：
ALAN R. SALTIEL
金额：
$ 52.54万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10187564
关键词：
ASCL1 gene Acute Acyl Coenzyme A Adaptor Signaling Protein Affinity Apoptosis Apoptotic Attention Binding Biological CASP6 gene CRISPR/Cas technology Cells Cessation of life Coenzyme A Ligases Complex Data Diabetes Mellitus Diet Disease Ensure Enzymes Epidemic Equilibrium Esterification Event Exhibits Family member Fasting Fatty Acids Fatty Liver Fatty acid glycerol esters Gene Expression Genetic Transcription Hepatic Hepatitis Hepatocyte High Fat Diet Homeostasis Human In Vitro Inflammation Inflammatory Insulin Resistance Investigation Knock-in Knock-out Knockout Mice Link Lipids Liver Metabolic Metabolism Mitochondria Molecular Molecular Conformation Mus Mutation Analysis Nature Obese Mice Obesity Obesity Epidemic Outer Mitochondrial Membrane Pathology Pathway interactions Patients Phosphorylation Phosphotransferases Play Process Protein Family Protein Kinase Protein Serine/Threonine Phosphatase Proteins Regulation Repression Role Scaffolding Protein Signal Transduction Site Starvation TBK1 gene Time Uncertainty amlexanox cytokine energy balance fatty acid oxidation in vivo inhibitor/antagonist lipid metabolism liver injury mimetics mutant non-alcoholic non-alcoholic fatty liver disease novel therapeutic intervention oxidation prevent reconstitution recruit restoration upstream kinase

项目摘要

Abstract There is little doubt that we are in the midst of a worldwide epidemic of obesity and diabetes. Among the many complications of obesity is fatty liver, and its associated disease Nonalcoholic Steatotic Hepatitis (NASH). However, the manner by which lipid storage and oxidation is controlled in liver is only partly understood. We hypothesize that inflammation plays a role in this process through the protein kinase TBK1. TBK1 associates with the key enzyme ACSL1, localizing it to mitochondria for fatty acid oxidation during starvation, and to ER for fatty acid re-esterification during obesity. Moreover, TBK1 represses the activity of AMPK during obesity, linking fatty liver to liver damage. We will explore the nature of these pathways with three aims: 1) We will elucidate the temporal and spatial aspects of the induction and activation of the kinase TBK1 in fasting and obesity; 2) We will deeply explore the molecular mechanism involved in its interaction with ACSL1; and 3) We will evaluate the molecular mechanisms whereby TBK1 reduces the activity of AMPK, and how this results in hepatocellular death and liver damage.

抽象的毫无疑问，我们正处于肥胖和糖尿病的全球流行病中。在许多人中肥胖症的并发症是脂肪肝，其相关疾病非酒精性脂肪性肝炎（NASH）。但是，只能部分理解在肝脏中控制脂质储存和氧化的方式。我们假设炎症通过蛋白激酶TBK1在此过程中起作用。 TBK1协会使用钥匙酶ACSL1，将其定位在饥饿期间的线粒体中进行脂肪酸氧化，并将其定位用于肥胖期间脂肪酸的重新酯化。此外，TBK1抑制肥胖期间AMPK的活性，将脂肪肝与肝脏损伤联系起来。我们将以三个目标探索这些途径的性质：1）我们将阐明在禁食中激酶TBK1的诱导和激活的时间和空间方面肥胖; 2）我们将深入探索与ACSL1相互作用所涉及的分子机制； 3）我们将评估TBK1降低AMPK活性的分子机制，以及这如何导致肝细胞死亡和肝脏损害。