Coordination of hepatic fatty acid metabolism

肝脏脂质合成、摄取、输出和氧化的平衡在其进展中起着重要作用。 和代谢综合征的发病机制，对于日益增长的发病率尤为重要 非酒精性脂肪性肝炎(NASH)然而，控制从正常代谢转变的机制 生理学对病理生理学了解甚少，尤其是关于脂类代谢的作用。 我们的总体目标是确定肝脏如何感知和响应脂肪酸可利用性的波动 促进关键过程，如糖异生和酮生，并了解如何靶向脂质 新陈代谢可以保护或加强肥胖、糖尿病和NASH。我们已经开发了多个鼠标 在肝脏独特的代谢节点处扰乱脂肪酸分解代谢的模型。我们已经证明，尽管 所有这些模型都表现为脂肪肝，并存在于假定的脂肪酸氧化的线性途径中，它们 表现出惊人的独特的细胞和分子表型。这些数据表明，甘油三酯 水解和脂肪酸氧化向肝细胞传递独特的生化信息，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的调控密码，我们提出了三个 具体目的是：1)确定甘油三酯水解和脂肪酸氧化的独立作用 禁食，2)确定甘油三酯水解和脂肪酸的独立和相互依赖的作用 氧化在高脂饮食诱导的肥胖中的作用和3)确定脂肪酸依赖的赖氨酸乙酰化在 调节肝脏代谢。在这里，我们将使用这些模型来了解新陈代谢代码 脂肪酸影响肝脏脂肪代谢的协调性。

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.