权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

项目总结/文摘