Transcriptional Regulation of Metabolism

描述(申请人提供)：肥胖与非酒精性脂肪性肝病(NAFLD)有关。NAFLD是胰岛素抵抗和心血管疾病的危险因素，并导致非酒精性脂肪性肝炎(NASH)、肝硬变和肝功能衰竭。肝脏脂肪变性被认为是“第一次打击”，而“第二次打击”(如氧化、内质网和氧化应激)也是NAFLD/NASH进展所必需的。然而，第一次和第二次击中之间的相互作用以及NAFLD/NASH进展的潜在机制仍不清楚。在初步研究中，我们发现Snail2是一种新的脂代谢调节剂，在肥胖的NAFLD中是必需的。Snail2是一种转录调节因子，被认为在发育和癌症转移过程中促进上皮向间充质转化(EMT)。它还可能调节某些细胞类型的增殖和凋亡；然而，在这项工作之前，它的代谢功能还没有被探索过。我们发现肥胖时肝脏Snail2的表达显著增加。Snail2的基因缺失可预防NAFLD，减少肝脏氧化、内质网和炎症应激，并改善饮食或遗传肥胖小鼠的胰岛素抵抗和葡萄糖耐量。Snail2似乎执行双重作用，抑制与脂肪酸氧化有关的基因，并激活与脂肪合成和摄取有关的基因。在目前的研究中，我们将通过建立和鉴定肝细胞特异性Snail2基因敲除或过度表达的小鼠，来巩固这些观察结果，以确定肝脏Snail2在NAFLD进展和胰岛素抵抗中的重要作用。我们将确定代谢、氧化、内质网和炎症应激是否增加了肝脏Snail2的水平(通过转录和稳定性)和活性(通过翻译后修饰)，这反过来又通过增加脂肪合成和脂质摄取以及减少氧化来促进脂肪变性。我们将确定肝脏Snail2是否连接第一次和第二次打击，并形成肝细胞应激-Snail2恶性循环，推动NAFLD在肥胖中的进展。我们将阐明肝脏Snail2激活或抑制控制脂肪合成、脂肪吸收和氧化的基因的机制，并验证肝脏Snail2在肥胖背景下对脂质途径进行基因重组的假说。这项研究的影响在于建立了一种新的代谢功能 并测试肝细胞应激-Snail2恶性循环驱动NAFLD进展的新概念。这一结果有望通过靶向肝脏Snail2来导致治疗NAFLD的新疗法。

DESCRIPTION (provided by applicant): Obesity is associated with nonalcoholic fatty liver disease (NAFLD). NAFLD is a risk factor for insulin resistance and cardiovascular diseases, and leads to nonalcoholic steatohepatitis (NASH), cirrhosis, and liver failure. Hepatic steatosis is believed to be "the first hit", and "the second hit" (e.g. oxidative, ER and oxidative stress) is aso required for NAFLD/NASH progression. However, the interplay of the first and second hits and the underlying mechanism of NAFLD/NASH progression remain unclear. In the preliminary study, we identified Snail2 as a novel regulator of lipid metabolism that is required for NAFLD in obesity. Snail2 is a transcriptional regulator believed to promote epithelial-to-mesenchymal transition (EMT) in development and cancer metastasis. It may also regulate proliferation and apoptosis in some cell types; however, its metabolic function has not been explored prior to this work. We show that the expression of hepatic Snail2 markedly increases in obesity. Genetic deletion of Snail2 prevents NAFLD, reduces liver oxidative, ER, and inflammatory stress, and improves insulin resistance and glucose intolerance in mice with either dietary or genetic obesity. Snail2 appears to perform dual actions, repressing the genes involved in fatty acid oxidation and activating the genes involved in lipid synthesis and uptake. In the current study, we will extend these observations to firmly establish the essential role of hepatic Snail2 in NAFLD progression and insulin resistance by generating and characterizing hepatocyte-specific Snail2 knockout or overexpressing mice. We will determine whether metabolic, oxidative, ER, and inflammatory stress increase the levels (via transcription and stability) and activity (via posttranslational modifications) of hepatic Snail2, which in turn promotes steatosis by increasing lipid synthesis and lipid uptake and decreasing oxidation. We will determine whether hepatic Snail2 connects the first and the second hits, and forms a hepatocellular stress-Snail2 vicious cycle that drives NAFLD progression in obesity. We will elucidate the mechanism by which hepatic Snail2 activates or represses the genes that control lipid synthesis, lipid uptake, and oxidation, and test the hypothesis that hepatic Snail2 genetically reprograms lipid pathways in the setting of obesity. The impact of this study lies in establishing a novel metabolic function of hepatic Snail2 and testing the novel concept that the hepatocellular stress-Snail2 vicious cycle drives NAFLD progression. The outcome is expected to lead to new therapies for NAFLD by targeting hepatic Snail2.