Inflammation and hepatic lipid metabolism

摘要 毫无疑问，我们正处于肥胖和糖尿病的全球流行之中。在众多的 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的控制方式只有部分了解。我们 假设炎症通过蛋白激酶TBK1在这一过程中发挥作用。TBK1员工 通过关键酶ACSL1，将其定位于线粒体，在饥饿期间进行脂肪酸氧化，并定位到内质网 用于肥胖期间的脂肪酸再酯化。此外，TBK1在肥胖过程中抑制AMPK的活性， 把脂肪肝和肝脏损伤联系起来。我们将以三个目标探索这些途径的性质：1)我们将 阐明在空腹和非饥饿状态下诱导和激活蛋白酪氨酸激酶1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。

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.