An NADH-ChREBP axis in fatty liver disease and dyslipidemia

脂肪肝疾病和血脂异常中的 NADH-ChREBP 轴

• 批准号: 10564369
• 负责人: Russell Paul Goodman
• 金额: $ 53.78万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-15 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10564369
• 关键词: Alcoholic Fatty Liver; Alcohols; Candidate Disease Gene; Cardiovascular Diseases; Cell Culture Techniques; Cirrhosis; Data; Dependence; Development; Disease; Dyslipidemias; Engineering; FGF21 gene; Fatty Liver; Fatty acid glycerol esters; Genes; Genetic; Genetic Determinism; Genetic Transcription; Genotype; Goals; Hepatic; Human; Human Engineering; Human Genetics; Hydroxybutyrates; Knowledge; Life; Lipids; Liver; Liver diseases; Measures; Medical; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolic stress; Metabolism; Mission; Modeling; Morbidity - disease rate; Mus; NADH; Nature; Organoids; Oxidation-Reduction; Pathogenicity; Phenotype; Post-Translational Protein Processing; Public Health; Publishing; Reaction; Research; Role; Source; Stress; Testing; Therapeutic; Time; Transcriptional Activation; Transgenic Organisms; United States; United States National Institutes of Health; Variant; Work; circulating biomarkers; cofactor; cohort; experimental study; fatty liver disease; fibroblast growth factor 21; genome wide association study; heart metabolism; improved; in vivo; inhibitor; innovation; insight; liver transplantation; metabolic abnormality assessment; mortality; mouse model; non-alcoholic fatty liver; non-alcoholic fatty liver disease; novel; novel strategies; novel therapeutic intervention; novel therapeutics; pharmacologic; pleiotropism; therapeutic target; tool; trait; transcription factor; transcriptome sequencing

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.

项目总结/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）没有有效的药物治疗。我们必须更好地了解这些的代谢原因 开发新疗法的条件。这项工作的长期目标是了解肝细胞癌是如何升高的。 NADH水平影响代谢，导致致病性代谢特征，如脂肪肝和血脂异常， 并利用这一洞察力来开发针对这些疾病的新疗法。我们发现， 是AFLD、NAFLD和一种常见的GCKR P446 L变异的特征， 人类通过使用一种新的代谢工具LbNOX来改变小鼠肝脏的NADH水平，我们发现， NADH激活脂肪生成转录因子ChREBP。我们的总体目标是确定 升高的肝NADH导致肝脂肪积累和血脂异常。我们的核心假设是， 升高的NADH水平是导致肝脏脂肪积聚和血脂异常的常见机制， NAFLD和AFLD通过激活转录因子ChREBP而发生，并且肝脏NADH可以被激活。 直接针对有益的代谢效果。这一建议的基本原理是， 在NAFLD的发展中起着偶然的作用，而AFLD将证实降低肝脏NADH作为治疗NAFLD的有效方法。 治疗策略来治疗这些病症。我们的中心假设将通过追求三个具体的测试 目的：（1）明确GCKR依赖于ChREBP和NADH的转录和代谢作用 446 L通过使用人类肝脏类器官（HLO），我们已经设计了不同的GCKR 基因型(2)我们将确定NADH-ChREBP轴在NAFLD小鼠模型中的体内作用， 使用新产生的转基因LbNOX小鼠的AFLD。(3)我们将确定新的基因调节剂， 使用大规模遗传学方法研究肝脏NADH及其在肝脏脂肪和ChREBP活化之间关系 不同的远系繁殖小鼠队列。所提出的工作是重要的，因为证明NADH的作用- 脂肪肝疾病中的ChREBP轴将激发直接针对肝脏NADH的新治疗策略。这 这项工作是创新的，因为它结合了新的代谢工具和方法来研究代谢疾病 - 包括转基因LbNOX小鼠和人类肝脏类器官-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。