HDAC1 as a nutrient sensor in the development and progression of NAFLD

非酒精性脂肪性肝病(NAFLD)是一种日益严重的代谢紊乱，与 肥胖和胰岛素抵抗/2型糖尿病。NAFLD以简单的肝脏脂肪变性开始，在一些 个体可能进展为非酒精性脂肪性肝炎(NASH)，这是一种晚期异常，可能进一步导致 肝纤维化、肝硬变、肝功能衰竭或癌症。而增强的从头脂肪生成和脂肪酸内流启动 肝脏脂肪变性，肝脏炎症触发从肝脏脂肪变性向NASH的转变，是一种 是肝纤维化病理进展的重要推动力。然而，确切的机制是 NAFLD的发展和进展的根本原因仍然知之甚少。虽然众多的研究 致力于评估与肥胖及其相关并发症有关的遗传因素，如 作为非酒精性脂肪肝，这一过程中的表观遗传学变化尚不清楚。表观遗传调控，包括组蛋白 乙酰化，是环境因素(例如饮食)和复杂疾病(例如NAFLD)之间的分子联系。 组蛋白脱乙酰酶1(HDAC1)作用于去除组蛋白中赖氨酸残基上的乙酰基，从而 抑制基因表达。我们的初步数据表明，肝脏特异性的HDAC1缺失减少 小鼠肝脏脂质堆积、炎症和纤维化。因此，我们假设HDAC1扮演一个 在NAFLD发展中的核心作用。目标1将确定HDAC1在促肝作用中的作用 脂肪变性。我们已经建立了肝脏特异性HDAC1缺失或过表达的遗传模型。我们会 确定：1)肝脏特异性HDAC1缺失是否以及如何预防，而肝脏特异性HDAC1过度表达 HDAC1促进小鼠肝脏脂肪变性；2)转录抑制因子KLF3是否下调 通过调节PPARγ，介导HDAC1促进肝脏脂肪储存的作用。目标2将决定 HDAC1促进肝脏炎症在NASH发生发展中的作用肝脏炎症引发 从肝脏脂肪变性到NASH的转变。我们将确定：1)肝脏特异缺失HDAC1 防止，而HDAC1的特异性过表达促进小鼠的NASH；2)下调 转录抑制因子KLF3介导HDAC1促进肝脏趋化作用 C-jun参与炎症反应的调节。目标3将通过以下方式确定HDAC1的潜在调控机制 营养过剩。O-GlcN酰化已成为调节细胞代谢的关键营养感受器 对过度营养线索作出反应的途径。我们将确定HDAC1 O-GlcN酰化是否过量 营养物质，如葡萄糖和饱和脂肪酸，在肥胖者中通常水平升高，增加 通过防止泛素化和蛋白酶体降解来稳定HDAC1蛋白，导致HDAC1增强 蛋白质含量和活性。该项目将确定HDAC1作为调节肝脏的营养传感器的作用 脂代谢与炎症在非酒精性脂肪肝发生发展中的作用我们的研究可以指导 表观遗传调控作为NAFLD治疗新靶点的研究进展

Non-alcoholic fatty liver disease (NAFLD) is a growing metabolic disorder that is closely associated with obesity and insulin resistance/type 2 diabetes. NAFLD begins with a simple hepatic steatosis, which in some individuals may progress to nonalcoholic steatohepatitis (NASH), an advanced abnormity that may further lead to fibrosis, cirrhosis, liver failure or cancer. Whereas enhanced de novo lipogenesis and fatty acid influx initiate the hepatic steatosis, hepatic inflammation triggers the transition from hepatic steatosis to NASH and is an important driving force of the pathological progression towards fibrogenesis. However, the exact mechanisms underlying the development and progression of NAFLD remain poorly understood. While numerous studies have been devoted to the evaluation of genetic factors involved in obesity and its associated complications such as NAFLD, much is unknown about epigenetic changes in this process. Epigenetic regulation, including histone acetylation, is a molecular link between environmental factors (e.g., diets) and complex diseases (e.g., NAFLD). Histone deacetylase 1 (HDAC1) acts to remove acetyl groups from lysine residues in histones, thereby inhibiting gene expression. Our preliminary data suggested that liver-specific deletion of HDAC1 decreased hepatic lipid accumulation, inflammation and fibrosis in mice. Therefore, we hypothesize that HDAC1 plays a central role in the development of NAFLD. Aim 1 will determine the role of HDAC1 in promoting hepatic steatosis. We have generated genetic models with liver specific deletion or overexpression of HDAC1. We will determine: 1) whether and how liver-specific deletion of HDAC1 prevents, whereas specific overexpression of HDAC1 promotes hepatic steatosis in mice; 2) whether down-regulation of the transcriptional repressor KLF3 mediates the effect of HDAC1 in promoting hepatic lipid storage via regulation of PPARγ. Aim 2 will determine the role of HDAC1 in promoting hepatic inflammation in the development of NASH. Hepatic inflammation triggers the transition from hepatic steatosis to NASH. We will determine: 1) whether liver-specific deletion of HDAC1 prevents, whereas specific overexpression of HDAC1 promotes NASH in mice; 2) whether down-regulation of the transcriptional repressor KLF3 mediates the effect of HDAC1 in promoting hepatic chemotaxis and inflammation via regulation of C-Jun. Aim 3 will determine the mechanism underlying regulation of HDAC1 by excess nutrients. O-GlcNAcylation has emerged as a key nutrient sensor that regulates cellular metabolic pathways in response to over-nutritional cues. We will determine whether HDAC1 O-GlcNAcylation by excess nutrients such as glucose and saturated fatty acids, levels of which are commonly elevated in obesity, increases HDAC1 protein stability by preventing ubiquitination and proteasomal degradation, leading to enhanced HDAC1 protein content and activity. This project will define the role of HDAC1 as a nutrient sensor that regulates hepatic lipid metabolism and inflammation in the development and progression of NFALD. Our studies could guide the development of the epigenetic regulation as new therapeutic targets in the treatment of NAFLD.