Hepatic Integration of Mitochondrial Oxidative Metabolism Pathways in Health and Disease

健康和疾病中线粒体氧化代谢途径的肝脏整合

基本信息

批准号：
10716755
负责人：
Curtis Hughey
金额：
$ 41.03万
依托单位：
UNIVERSITY OF MINNESOTA
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：
2023-07-01 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10716755
关键词：
3-hydroxy-3-methylglutaryl-coenzyme A Acute Adult Biological Assay Cardiometabolic Disease Catabolism Cell Respiration Chronic Cirrhosis Citric Acid Cycle Coupling Data Diet Disease Disease Management Disease stratification Enzymes Exercise Exhibits Fatty Liver Fatty acid glycerol esters Fibrosis Fluorometry Free Radicals Health Hepatic Heterogeneity High Fat Diet Human Human Characteristics Impairment Inflammation Intervention Isotopes Ketone Bodies Ketones Knockout Mice Knowledge Lead Lecithin Lipids Liver Liver Mitochondria Liver diseases Metabolic Methods Mitochondria Molecular Mus NADH Nicotinamide N-Methyltransferase Nutrient Outcome Oxidative Phosphorylation Oxidative Stress Oxidoreductase Pathologic Pathway interactions Phenotype Phosphatidylethanolamine N-Methyltransferase Primary carcinoma of the liver cells Production Protocols documentation Public Health Research Rest Risk Running Severity of illness Signal Transduction Spirometry Steatohepatitis Testing United States Wild Type Mouse Work beta-Hydroxybutyrate chronic liver disease exercise training improved in vivo indexing innovation islet amyloid polypeptide ketogenesis ketogenic diet ketogentic knock-down liver injury metabolomics mouse model nicotinamide riboside supplementation nicotinamide-beta-riboside non-alcoholic fatty liver disease nonalcoholic steatohepatitis novel therapeutics oxidation preservation prevent response treadmill

项目摘要

Non-alcoholic fatty liver disease (NAFLD), including non-alcoholic steatohepatitis (NASH), is the most common liver disease in the United States and it increases the risk for cirrhosis and hepatocellular carcinoma. Prior research shows that dysregulated lipid partitioning in liver mitochondrial oxidative metabolism pathways [i.e., tricarboxylic acid (TCA) cycle, oxidative phosphorylation (OXPHOS), and ketogenesis] is fundamental to liver steatosis and oxidative stress that underlie NAFLD. A traditional view of mitochondrial lipid partitioning is that lipids are fated to ketogenesis when the capacity of terminal oxidation (TCA cycle and OXPHOS) is exceeded, but ketogenesis is limited when the TCA cycle and OXPHOS can support terminal oxidation or under states of high hepatic energy demand. However, this dualist view of lipid partitioning fails to describe heterogeneity in mitochondrial function across the NAFLD spectrum and reveals knowledge gaps in our understanding of how liver mitochondria may coordinate lipid catabolism. The objective of this project is to test the innovate premise that ketogenesis actively supports TCA cycle function and that loss of this salutary coupling contributes to NAFLD. This is based on our preliminary data from mouse models of varying NAFLD severity. Initial studies used phosphatidylethanolamine N-methyltransferase (PEMT)-null mice that exhibit NASH owing to reduced phosphatidylcholine, which is characteristic of human NASH. PEMT-null mice showed lower liver NAD+ and molecular indices of terminal oxidation, however, in vivo TCA cycle flux was unaltered and ketogenesis was increased. This phenotype in mice mimics our preliminary data in humans with NASH which showed elevated ketogenesis and preserved TCA cycle flux. Notably, PEMT-null mice fed a high-fat diet and wild type mice fed a ketogenic diet had lower liver nicotinamide N-methyltransferase (NNMT), which may lead to greater NAD+ salvage to facilitate TCA cycle flux that would otherwise be impaired. In addition, knockdown of ketogenic enzyme 3-hydroxymethylglutaryl-CoA synthase 2 (HMGCS2) in mice on a high-fat diet resulted in lower liver ketogenesis (as expected) and NAD+. Our central hypothesis is that ketogenesis enhances TCA cycle flux via acute and chronic NAD+ provision under conditions of excess lipid availability. This hypothesis will be tested via two Specific Aims. Aim 1 will demonstrate that a ketone body-NNMT-NAD+ axis mitigates liver steatosis by promoting TCA cycle flux in NASH. Mice lacking liver HMGCS2 will receive a Gubra Amylin NASH (GAN) diet and will be independently crossed with liver-specific NNMT knockout mice or provided nicotinamide riboside to increase NAD+. Aim 2 will determine that an increased NAD+/NADH ratio supported by ketogenesis facilitates lipid disposal in response to exercise. HMGCS2 and β-hydroxybutyrate dehydrogenase 1 will be deleted in livers of mice fed a GAN diet to impede ketogenesis and NAD+ provision. Acute and chronic exercise protocols will be completed. Impact: This project will lead progress in creating a paradigm shift by advancing our understanding of how ketogenesis facilitates lipid disposal and informing new therapies for preventing NASH.

非酒精性脂肪肝（NAFLD），包括非酒精性脂肪性肝炎（NASH），是最常见的疾病在美国，它会增加肝硬化和肝细胞癌的风险。研究表明，肝脏线粒体氧化代谢途径中的脂质分配失调[即，三羧酸（TCA）循环、氧化磷酸化（OXPHOS）和生酮]是肝脏的基础 NAFLD 背后的脂肪变性和氧化应激是线粒体脂质分配的传统观点。当超过末端氧化（TCA 循环和 OXPHOS）的能力时，脂质注定会生酮，但当 TCA 循环和 OXPHOS 可以支持末端氧化或处于以下状态时，生酮受到限制然而，这种分配脂质的二元论观点未能描述肝脏的异质性。线粒体在 NAFLD 谱系中的功能，并揭示了我们在理解线粒体功能方面的知识差距肝脏线粒体可以协调脂质分解代谢，该项目的目的是测试创新前提。生酮积极支持 TCA 循环功能，而这种有益耦合的丧失会导致 NAFLD。这是基于我们对不同 NAFLD 严重程度的小鼠模型的初步数据。使用磷脂酰乙醇胺 N-甲基转移酶 (PEMT) 缺失的小鼠，由于减少的磷脂酰胆碱是人类 NASH 缺失小鼠的特征，其肝脏 NAD+ 和 NAD+ 水平较低。然而，末端氧化的分子指数，体内 TCA 循环通量没有改变，生酮作用也发生了变化。小鼠中的这种表型模仿了我们在患有 NASH 的人类中的初步数据，该数据显示出升高。生酮和保留的 TCA 循环通量值得注意的是，PEMT 无效小鼠喂食高脂肪饮食，而野生型小鼠喂食。生酮饮食的肝脏烟酰胺 N-甲基转移酶 (NNMT) 较低，这可能导致 NAD+ 水平较高挽救，以促进否则会受损的 TCA 循环通量。此外，还可以抑制生酮。高脂饮食小鼠体内的 3-羟甲基戊二酰辅酶 A 合酶 2 (HMGCS2) 导致肝脏功能降低生酮（如预期）和 NAD+ 我们的中心假设是生酮通过增强 TCA 循环通量。在脂质可用性过剩的情况下，急性和慢性 NAD+ 供应将得到检验。通过两个具体目标 1 将证明酮体-NNMT-NAD+ 轴通过以下方式减轻肝脏脂肪变性。促进 NASH 中 TCA 循环通量缺乏肝脏 HMGCS2 的小鼠将接受 Gubra Amylin NASH (GAN) 饮食。并将与肝脏特异性 NNMT 敲除小鼠独立杂交或提供烟酰胺核苷增加 NAD+ 目标 2 将确定增加的 NAD+/NADH 比例有利于生酮作用。 HMGCS2 和 β-羟基丁酸脱氢酶 1 将被删除。喂食 GAN 饮食以阻碍生酮和 NAD+ 供给的小鼠肝脏急性和慢性运动方案。影响：该项目将通过推进我们的工作来引领范式转变。了解生酮如何促进脂质处理，并为预防 NASH 的新疗法提供信息。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Exercise training adaptations in liver glycogen and glycerolipids require hepatic AMP-activated protein kinase in mice.

小鼠肝糖原和甘油脂的运动训练适应性需要肝 AMP 激活蛋白激酶。

DOI：
发表时间：
2024-01-01
期刊：
影响因子：
0
作者：
Hughey, Curtis C;Bracy, Deanna P;Rome, Ferrol I;Goelzer, Mickael;Donahue, E Patrick;Viollet, Benoit;Foretz, Marc;Wasserman, David H
通讯作者：
Wasserman, David H