Inflammation and hepatic lipid metabolism

炎症与肝脏脂质代谢

• 批准号: 10033511
• 负责人: ALAN R. SALTIEL
• 金额: $ 52.38万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 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/10033511
• 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; Estrogen receptor positive; 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

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，我们正处于全球肥胖和糖尿病流行之中。在众多之中 肥胖的并发症是脂肪肝，及其相关疾病非酒精性脂肪性肝炎(NASH)。 然而，人们对肝脏中脂质储存和氧化控制的方式只有部分了解。我们 假设炎症通过蛋白激酶 TBK1 在此过程中发挥作用。 TBK1 同事 与关键酶 ACSL1 结合，将其定位于线粒体以在饥饿期间进行脂肪酸氧化，并定位于 ER 用于肥胖期间脂肪酸的再酯化。此外，TBK1 在肥胖期间抑制 AMPK 的活性， 将脂肪肝与肝损伤联系起来。我们将探索这些途径的本质，以实现三个目标：1）我们将 阐明禁食和禁食中激酶 TBK1 诱导和激活的时间和空间方面 肥胖; 2）深入探讨其与ACSL1相互作用的分子机制； 3）我们 将评估 TBK1 降低 AMPK 活性的分子机制，以及这如何导致 肝细胞死亡和肝损伤。