Coordination of hepatic fatty acid metabolism

肝脏脂肪酸代谢的协调

• 批准号: 10116890
• 负责人: Michael J. Wolfgang
• 金额: $ 40.94万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10116890
• 关键词: Acetylation; Adipocytes; Affect; Biochemical; Carnitine Palmitoyltransferase I; Catabolism; Code; Communication; Coupling; Data; Diabetes Mellitus; Diet; Energy Metabolism; Equilibrium; Exhibits; Fasting; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Functional disorder; Gene Expression; Genetic Transcription; Gluconeogenesis; Goals; Hepatic; Hepatocyte; High Fat Diet; Histone Acetylation; Hydrolysis; Incidence; Inflammation; Knockout Mice; Lead; Lipase; Lipids; Lipoproteins; Liver; Lysine; Metabolic; Metabolic stress; Metabolic syndrome; Metabolism; Mitochondria; Modeling; Mus; Obesity; Oxidative Stress; PPAR alpha; Pathogenesis; Pathology; Pathway interactions; Phenotype; Physiology; Play; Process; Proteins; Proteomics; Regulation; Role; Route; Signal Transduction; Starvation; Triglyceride Metabolism; Triglycerides; detection of nutrient; fatty acid metabolism; fatty acid oxidation; feeding; ketogenesis; lipid metabolism; liver metabolism; long chain fatty acid; molecular phenotype; mouse model; nonalcoholic steatohepatitis; novel therapeutic intervention; oxidation; response; uptake

The balance of hepatic lipid synthesis, uptake, export and oxidation plays an important role in the progression and pathogenesis of the metabolic syndrome and is particularly important for the growing incidence of Nonalcoholic Steatohepatitis (NASH). However, the mechanisms governing the shift from normal metabolic physiology to pathophysiology are poorly understood, particularly with respect to the role of lipid metabolism. Our overall goal is to determine how the liver senses and responds to fluctuations in fatty acid availability to facilitate key processes such as gluconeogenesis and ketogenesis, and to understand how targeting lipid metabolism could either protect or potentiate obesity, diabetes and NASH. We have developed multiple mouse models that disrupt fatty acid catabolism at unique metabolic nodes in the liver. We have shown that although all of these models exhibit fatty liver and exist in a putative linear pathway for the oxidation of fatty acids, they exhibit surprisingly unique cellular and molecular phenotypes. These data demonstrate that both triglyceride hydrolysis and fatty acid oxidation convey unique biochemical information to the hepatocyte to coordinate the catabolism of fatty acids. To describe this unique fatty acid dependent regulatory code, we propose three specific aims to 1) Determine the independent roles for triglyceride hydrolysis and fatty acid oxidation during fasting, 2) Determine the independent and interdependent roles of triglyceride hydrolysis and fatty acid oxidation in HFD-induced obesity and 3) Determine the role of fatty acid-dependent lysine acetylation in the regulation of hepatic metabolism. Here we will use these models to understand the metabolic code by which fatty acids affect the hepatic coordination of lipid metabolism.

肝脂质合成，摄取，出口和氧化的平衡在进展中起重要作用 和代谢综合征的发病机理，对于不断增长的发生率尤为重要 非酒精性脂肪性肝炎（NASH）。但是，管理从正常代谢转变的机制 病理生理学的生理学知之甚少，特别是在脂质代谢的作用方面。 我们的总体目标是确定肝脏感官的感官和响应脂肪酸的波动如何 促进关键过程，例如糖异生和生酮发生，并了解靶向脂质的方式 代谢可以保护或增强肥胖，糖尿病和纳什。我们已经开发了多个鼠标 在肝脏中独特的代谢节点上破坏脂肪酸分解代谢的模型。我们已经证明了，尽管 所有这些模型都表现出脂肪肝，并存在于脂肪酸氧化的推定线性途径中 表现出令人惊讶的独特细胞和分子表型。这些数据表明两个甘油三酸酯 水解和脂肪酸氧化将独特的生化信息传达给肝细胞，以协调 脂肪酸的分解代谢。为了描述这种独特的脂肪酸依赖性调节代码，我们提出了三个 1）确定在甘油三酸酯水解和脂肪酸氧化过程中的独立作用 禁食，2）确定甘油三酸酯水解和脂肪酸的独立和相互依存的作用 HFD诱导的肥胖症中的氧化和3）确定脂肪酸依赖性赖氨酸乙酰化在 调节肝代谢。在这里，我们将使用这些模型了解代谢代码 脂肪酸会影响脂质代谢的肝配位。