Transcriptional Regulation of Metabolism

描述（由申请人提供）：肥胖与非酒精性脂肪性肝病（NAFLD）相关。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）、肝硬化和肝功能衰竭。肝脂肪变性被认为是“第一击”，而“第二击”（如氧化、内质网和氧化应激）也是NAFLD/NASH进展所必需的。然而，第一次和第二次撞击的相互作用以及NAFLD/NASH进展的潜在机制仍不清楚。在初步研究中，我们发现Snail2是一种新的脂质代谢调节剂，是肥胖NAFLD所必需的。Snail2是一种转录调节因子，被认为在肿瘤发育和转移过程中促进上皮细胞向间充质细胞转化（EMT）。它还可能调节某些细胞类型的增殖和凋亡；然而，在此之前，其代谢功能尚未被探索。我们发现肝脏Snail2的表达在肥胖中显著增加。Snail2基因缺失可预防NAFLD，减少肝脏氧化、内质ER和炎症应激，并改善饮食性或遗传性肥胖小鼠的胰岛素抵抗和葡萄糖耐受不良。Snail2似乎具有双重作用，抑制参与脂肪酸氧化的基因，激活参与脂质合成和摄取的基因。在目前的研究中，我们将扩展这些观察结果，通过产生和表征肝细胞特异性Snail2敲除或过表达的小鼠，以牢固地确立肝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、ER和炎症应激是否会增加肝Snail2的水平（通过转录和稳定性）和活性（通过翻译后修饰），从而通过增加脂质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Snail2是否连接第一和第二打击，并形成肝细胞应激-Snail2恶性循环，驱动肥胖NAFLD进展。我们将阐明肝Snail2激活或抑制控制脂质合成、脂质摄取和氧化的基因的机制，并验证肝Snail2在肥胖背景下基因重编程脂质途径的假设。本研究的影响在于建立了一种新的代谢功能

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. PUBLIC HEALTH RELEVANCE: The prevalence of obesity is increasing rapidly. Obesity is associated with nonalcoholic fatty liver diseases (NAFLD). NAFLD leads to nonalcoholic steatohepatitis (NASH), cirrhosis, hepatocellular carcinoma, and type 2 diabetes. Unfortunately, the underlying mechanism of obesity-induced NAFLD is unclear, which limits our ability to treat these diseases. In this study, we will establish a novel concept that a "hepatocellular stress- Snail2 vicious cycle" drives NAFLD progression. Thus, the outcome is expected to lead to a new treatment for NAFLD, NASH, cirrhosis, and type 2 diabetes by breaking this cycle.