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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要/摘要尽管是肝病，酒精和非酒精性脂肪肝病（AFLD和AFLD和 NAFLD）没有有效的医疗疗法。我们必须更好地理解这些代谢原因开发新治疗的条件。这项工作的长期目标是了解肝的升高 NADH水平会影响代谢，导致致病代谢特征，例如脂肪肝和血脂异常，，并利用这种见解为这些条件开发新的治疗方法。我们发现NADH水平升高是AFLD，NAFLD和常见的GCKR P446L变体的特征，它导致肝脂肪积累人类。通过使用新的代谢工具LBNOX改变小鼠的肝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升高会导致肝脂肪积累和血脂异常。我们的中心假设是 NADH水平升高是导致肝脂肪积累和血脂异常的常见机制通过激活转录因子chrebp，nafld和afld可以是肝脏nadh 直接针对有益代谢作用。该提议的理由是显示nadh升高在NAFLD和AFLD的发展中起着偶然的作用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特定的测试目的：（1）我们将定义GCKR的CHREBP和NADH依赖性转录和代谢效应 446L通过使用人肝癌（HLOS），我们已经设计为具有不同的GCKR 基因型。（2）我们将确定NADH-CHREBP轴在NAFLD和使用新生成的转基因LBNOX小鼠的AFLD。（3）我们将确定升高的新型遗传调节剂肝NADH及其在肝脂肪和Chrebp激活之间使用大遗传学的关系潜水小鼠队列。提出的工作很重要，因为证明了nadh-的作用脂肪肝病中的Chrebp轴将激发直接针对肝NADH的新疗法策略。这工作具有创新性，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小鼠和人肝癌 - 以及从人类获得的见解理解和定义这种代谢途径的重要性的遗传学。