Role of Hepatic Fatty Acid Oxidation in Metabolic Homeostasis

肝脏是哺乳动物新陈代谢的中心，在为其他组织提供燃料方面发挥着关键作用，特别是在食物有限的情况下。线粒体脂肪酸β氧化具有不同先天错误的人在禁食后表现出危及生命的低酮症-低血糖，这是由于脂肪酸氧化在糖异生和酮生中的关键作用。为了了解肝脏脂肪酸氧化在全身代谢功能障碍中的作用，我们培育了不能通过线粒体β氧化来氧化长链脂肪酸的小鼠--通过有条件地缺失肉碱棕榈酰转移酶2(CPT2)，这是一个由单基因编码的专有步骤，在肝细胞中具有特异性。在这里，我们将利用这个模型来了解在禁食和高脂肪饮食挑战期间，脂肪酸氧化对肝脏和肝外调节系统代谢稳态的贡献。在此，我们提出了三个具体目标。1.确定空腹时肝脏脂肪酸氧化的需要量。2.确定肝脏脂肪酸氧化在高脂饮食诱导的体重和糖耐量中的作用。3.确定脂肪酸诱导转录的机制。长期目标是了解肝脏脂肪代谢在禁食和高脂饮食中的作用和要求。期望我们提出的研究将描述禁食时肝脏脂肪酸氧化的要求，以及肥胖和糖耐量减低的发展。此外，我们还将发现肝素和代谢信号在控制全身代谢生理学方面的新进展。

The liver is central to mammalian metabolism and plays a critical role in providing fuel to other tissues particularly when food is limiting. People with disparate inborn errors in mitochondrial fatty acid β-oxidation exhibit life-threatening hypoketotic-hypoglycemia following a fast due to the critical role of fatty acid oxidation to gluconeogenesis and ketogenesis. To understand the contribution of hepatic fatty acid oxidation to systemic metabolic dysfunction, we have generated mice that cannot oxidize long chain fatty acids via mitochondrial β-oxidation specifically in hepatocytes by the conditional deletion of Carnitine Palmitoyltransferase 2 (Cpt2), an obligate step encoded by a single gene. Here we will leverage this model to understand the contribution of fatty acid oxidation to hepatic and extrahepatic regulation of systemic metabolic homeostasis during fasting and high fat dietary challenges. Herein we propose three specific aims. 1. Determine the requirements of hepatic fatty acid oxidation during fasting. 2. Determine the role of hepatic fatty acid oxidation in high fat diet- induced body weight and glucose tolerance. 3. Determine the mechanism of fatty acid-induced transcription. The long-term goal is to understand the roles and requirements of hepatic lipid metabolism during fasting and high fat feeding. The expectation is that our proposed studies will describe the requirements of hepatic fatty acid oxidation in fasting and the development of obesity and glucose intolerance. Additionally, we will uncover new rolls for hepatokines and metabolic signaling in the control of systemic metabolic physiology.