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

非酒精性脂肪性肝病（NAFLD）是一种生长性代谢紊乱， 肥胖和胰岛素抵抗/2型糖尿病。NAFLD开始于简单的肝脂肪变性，在一些 个体可能进展为非酒精性脂肪性肝炎（NASH），这是一种晚期的abnormal，可能进一步导致 纤维化、肝硬化、肝衰竭或癌症。而增强的从头脂肪生成和脂肪酸流入启动 肝脏脂肪变性，肝脏炎症触发从肝脏脂肪变性到NASH的转变，并且是一种 纤维化的病理进展的重要驱动力。然而，确切的机制 对NAFLD的发展和进展的基础仍然知之甚少。虽然许多研究 一直致力于评估肥胖及其相关并发症的遗传因素， 与NAFLD一样，关于这一过程中的表观遗传变化还有很多未知之处。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）。 组蛋白脱乙酰基酶1（HDAC 1）用于从组蛋白中的赖氨酸残基去除乙酰基，从而 抑制基因表达。我们的初步数据表明，肝脏特异性HDAC 1缺失减少， 小鼠肝脏脂质蓄积、炎症和纤维化。因此，我们假设HDAC 1在 在NAFLD的发展中起着重要作用。目的1探讨HDAC 1在促进肝细胞凋亡中的作用 脂肪变性我们已经产生了肝脏特异性缺失或过度表达HDAC 1的遗传模型。我们将 确定：1）肝脏特异性HDAC 1缺失是否以及如何防止，而HDAC 1的特异性过表达 HDAC 1促进小鼠肝脂肪变性; 2）转录抑制因子KLF 3的下调是否 通过调节PPARγ介导HDAC 1促进肝脏脂质储存的作用。目标2将决定 HDAC 1在NASH发展中促进肝脏炎症的作用。肝脏炎症触发 从肝脂肪变性到NASH的转变。我们将确定：1）是否肝脏特异性缺失HDAC 1 预防，而HDAC 1的特异性过表达促进小鼠中的NASH; 2）是否下调HDAC 1的表达， 转录抑制因子KLF 3介导HDAC 1促进肝趋化性的作用， 目的3将确定HDAC 1通过调节C-Jun调节的潜在机制。 营养过剩O-GlcNAc酰化已成为调节细胞代谢的关键营养传感器 对过度营养的反应。我们将确定HDAC 1 O-GlcNAc酰化是否通过过量 营养素，如葡萄糖和饱和脂肪酸，其水平通常在肥胖症中升高， 通过防止泛素化和蛋白酶体降解，提高HDAC 1蛋白的稳定性， 蛋白质含量和活性。该项目将定义HDAC 1作为调节肝脏营养素的营养素传感器的作用。 脂质代谢和炎症的发展和进展的NCLD。我们的研究可以指导 发展表观遗传调控作为治疗NAFLD的新靶点。

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.