An NADH-ChREBP axis in fatty liver disease and dyslipidemia

项目摘要/摘要 尽管是最常见的肝病形式，但酒精和非酒精性脂肪性肝病(AFLD和 NAFLD)没有有效的药物疗法。我们必须更好地了解这些疾病的代谢原因。 开发新的治疗方法的条件。这项工作的长期目标是了解肝脏升高是如何 NADH水平影响代谢，导致病理性代谢特征，如脂肪肝和血脂异常， 并利用这一洞察力为这些疾病开发新的治疗方法。我们发现NADH水平升高 是AFLD、NAFLD的一个特征，也是一种常见的GCKR P446L变异，它会导致肝脏脂肪在 人类。通过使用一种新的代谢工具LbNOX来改变小鼠肝脏NADH水平，我们发现 NADH激活致脂转录因子ChREBP。我们的总体目标是确定如何 肝脏NADH升高导致肝脏脂肪堆积和血脂异常。我们的中心假设是 NADH水平升高是导致两者肝脏脂肪堆积和血脂异常的共同机制。 NAFLD和AFLD通过激活转录因子ChREBP，肝脏NADH可以 直接针对有益的代谢作用。这项提议的理由是，显示出NADH的升高 在NAFLD的发生和AFLD的发展中起到了偶然的作用，AFLD将验证降低肝脏NADH作为一种 治疗这些疾病的治疗策略。我们的中心假设将通过追求三个具体的 目标：(1)我们将确定GCKR的ChREBP和NADH依赖的转录和代谢效应 446L通过使用人类肝脏有机化合物(HLOS)，我们设计出了不同的GCKR 基因分型。(2)我们将确定NADH-ChREBP轴在NAFLD和NAFLD小鼠模型中的体内作用。 使用新产生的转基因LbNOX小鼠进行AFLD。(3)我们将寻找新的基因调控因子 肝脏NADH及其与肝脏脂肪和ChREBP激活的关系 不同的异种鼠群。拟议的工作具有重要意义，因为它展示了NADH的作用- CHREBP轴在脂肪性肝病中的作用将启发直接针对肝脏NADH的新的治疗策略。这 这项工作具有创新性，因为它结合了新的代谢工具和方法来研究代谢性疾病 -包括转基因LbNOX小鼠和人类肝脏器官-以及从人类获得的见解 遗传学来理解和定义这一代谢途径的重要性。

Project Summary/Abstract Despite being the most common forms of liver disease, alcohol and non-alcoholic fatty liver disease (AFLD and NAFLD) have no effective medical therapies. We must better understand the metabolic causes of these conditions to develop new treatments. The long term goal of this work is to understand how elevated hepatic NADH levels influence metabolism leading to pathogenic metabolic traits such as fatty liver and dyslipidemia, and use this insight to develop new treatments for these conditions. We have found that elevated NADH levels are a feature of AFLD, NAFLD, and a common GCKR P446L variant which causes hepatic fat accumulation in humans. By using a new metabolic tool, LbNOX, to alter hepatic NADH levels in mice we have found that NADH activates the lipogenic transcriptional factor ChREBP. Our overall objective is to determine how elevated hepatic NADH leads to hepatic fat accumulation and dyslipidemia. Our central hypothesis is that elevated NADH levels are a common mechanism leading to hepatic fat accumulation and dyslipidemia in both NAFLD and AFLD through activation of the transcription factor ChREBP, and that hepatic NADH can be directly targeted for beneficial metabolic effect. The rationale for this proposal is that showing elevated NADH has a casual role in the development of NAFLD and AFLD would validate lowering hepatic NADH as a therapeutic strategy to treat these conditions. Our central hypothesis will be tested by pursuing three specific aims: (1) We will define the ChREBP and NADH-dependent transcriptional and metabolic effects of GCKR 446L through the use of human liver organoids (HLOs) we have engineered to have different GCKR genotypes. (2) We will determine the in vivo role of an NADH-ChREBP axis in mouse models of NAFLD and AFLD using newly generated transgenic LbNOX mice. (3) We will identify novel genetic regulators of elevated hepatic NADH and their relationship between hepatic fat and ChREBP activation using a large genetically diverse outbred mouse cohort. The proposed work is significant because demonstrating the role of an NADH- ChREBP axis in fatty liver disease will inspire new therapeutic strategies directly targeting hepatic NADH. This work is innovative as it uses a combination of new metabolic tools and approaches to study metabolic disease – including transgenic LbNOX mice and human liver organoids – as well as insights gained from human genetics to understand and define the importance of this metabolic pathway.