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.

项目概要/摘要 尽管酒精和非酒精性脂肪肝病（AFLD 和 NAFLD）没有有效的药物治疗方法。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功能升高如何 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， 并利用这一见解来开发针对这些疾病的新疗法。我们发现 NADH 水平升高 是 AFLD、NAFLD 和常见的 GCKR P446L 变异的一个特征，该变异会导致肝脏脂肪堆积 人类。通过使用新的代谢工具 LbNOX 来改变小鼠肝脏 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 水平升高是导致肝脏脂肪堆积和血脂异常的常见机制 NAFLD 和 AFLD 通过转录因子 ChREBP 的激活，并且肝脏 NADH 可以 直接针对有益的代谢作用。该提案的基本原理是显示 NADH 升高 在 NAFLD 和 AFLD 的发展中具有偶然作用，将验证降低肝脏 NADH 作为一种 治疗这些病症的治疗策略。我们的中心假设将通过追求三个具体的 目标：（1）我们将定义 GCKR 的 ChREBP 和 NADH 依赖性转录和代谢效应 446L 通过使用人类肝脏类器官 (HLO)，我们设计出具有不同的 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 使用新生成的转基因 LbNOX 小鼠进行 AFLD。 (3) 我们将鉴定出新的遗传调节因子 肝脏 NADH 及其与肝脏脂肪和 ChREBP 激活之间的关系使用大遗传 多样化的近交小鼠群体。拟议的工作意义重大，因为展示了 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疾病 – 包括转基因 LbNOX 小鼠和人类肝脏类器官 – 以及从人类身上获得的见解 遗传学来理解和定义这种代谢途径的重要性。