Nutrient Overload, Insulin Resistance, and Hepatic Mitochondrial Dysfunction

营养过剩、胰岛素抵抗和肝线粒体功能障碍

基本信息

批准号：
10448125
负责人：
JAMAL A IBDAH
金额：
$ 18.88万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10448125
关键词：
Adipose tissue Aftercare Animals Bioenergetics Biogenesis Biopsy Biopsy Specimen Body Weight decreased Body mass index Caloric Restriction Cardiovascular Diseases Carnitine Palmitoyltransferase I Cirrhosis Clinical Management Data Diabetes Mellitus Diagnostic Disease Enzymes Event Exercise Exhibits Fasting Fatty Acids Fibrosis Functional disorder Gene Expression Generations Glucose Hepatic Histologic Histology Human Impairment In Vitro Individual Inflammation Insulin Insulin Resistance Isotopes Link Lipids Liver Liver Mitochondria Liver diseases Lobular Magnetic Resonance Spectroscopy Measurement Measures Mediating Mediator of activation protein Metabolic Methods Mitochondria Modeling Molecular Muscle Nutrient Obesity Pathogenicity Pathologic Pathology Patients Peripheral Phase Play Prevalence Primary Malignant Neoplasm of Liver Quality Control Regimen Risk Rodent Model Role Route Sampling Severity of illness Stress Testing Therapeutic Therapeutic Effect Time Tissue Sample Toxic effect Treatment Protocols Triglycerides VO2max Work active method advanced disease bariatric surgery cardiorespiratory fitness clinical care exercise training fatty acid oxidation glucose production human data imaging study improved insight intrahepatic lifestyle intervention lipid biosynthesis liver biopsy liver development liver metabolism mathematical model mitochondrial dysfunction mortality new therapeutic target non-alcoholic fatty liver disease nonalcoholic steatohepatitis oxidation response standard care theories treatment effect

项目摘要

Abstract Strong evidence from animal studies and indirect data from human imaging studies, implicate reduced liver mitochondrial activity as a key event in the pathophysiology of nonalcoholic steatohepatitis (NASH). Our preliminary data in NASH patients demonstrate that two treatments that relieve excess nutrient stress, caloric restriction (CR) and exercise training (EX), improve liver histology. Our recent studies in a rodent model established that the therapeutic effect of EX on liver histology is mediated through increases in both hepatic mitochondrial content and function. It is unknown whether a similar beneficial effect of such treatment on liver mitochondria occurs in humans. The central hypotheses of this project is that nutrient overload results in hepatic mitochondrial dysfunction, a key mediator of NASH pathology, and that amelioration of this overload will result in greater efficiency of mitochondrial bioenergetics and improved liver histology. To test these hypotheses, a treatment regimen combining CR and EX will be used to reduce intrahepatic triacylglycerols (IHTG) in 60 NASH patients. Baseline and 9-month liver biopsies in the treated group will be compared to repeat biopsies from 30 patients undergoing standard clinical management. We will complete the following specific aims. SA1 will utilize liver biopsy samples from patients with NASH, and liver samples obtained during bariatric surgery, to determine whether patients with more advanced liver disease have liver mitochondria that, in vitro and ex vivo, exhibit poor energy generation (quality control), biogenesis, and mitophagy; SA2 will isolate hepatic mitochondria again after 9-months to test whether loss of IHTG is associated with improved mitochondrial function, biogenesis and quality control as assessed by gene expression, enzyme levels and fatty acid oxidation. SA3 will measure whole body glucose and fatty acid flux in subjects under- going active treatment (CR+EX) and standard care. Measures will be made at baseline and after 9 months, and mathematical modeling used to quantitate peripheral nutrient disposal and the reduction in liver nutrient burden to compare its influence on mitochondrial function, fibrosis, and by the biopsy- determined NASH activity score using histological assessment. In summary, these studies will significantly advance the field of NAFLD through discoveries of 1) the mechanisms by which excess nutrient stress contributes to reduced hepatic mitochondrial function and 2) the relationships between mitochondrial activity and the histologic features of NASH. Importantly, this work will exert a sustained influence on the field by determining whether hepatic mitochondrial dysfunction is reversible in humans.

抽象的来自动物研究的有力证据和来自人类成像研究的间接数据表明，减少肝脏线粒体活性是非酒精性脂肪性肝炎病理生理学的关键事件（纳什）。我们在 NASH 患者中的初步数据表明，两种治疗方法可以缓解过量的营养应激、热量限制 (CR) 和运动训练 (EX)，改善肝脏组织学。我们最近的啮齿动物模型研究证实 EX 对肝脏组织学的治疗作用是介导的通过增加肝线粒体含量和功能。不知道是否有类似的这种治疗对人类肝线粒体产生有益作用。的中心假设该项目的观点是，营养过剩会导致肝线粒体功能障碍，这是线粒体功能障碍的关键介导因素。 NASH 病理学，并且改善这种过载将导致线粒体效率更高生物能量学和改善的肝脏组织学。为了检验这些假设，治疗方案结合了 CR 和 EX 将用于减少 60 名 NASH 患者的肝内三酰甘油 (IHTG)。基线治疗组 9 个月的肝活检将与 30 名患者的重复活检进行比较正在接受标准的临床管理。我们将完成以下具体目标。 SA1将利用 NASH 患者的肝活检样本以及减肥手术期间获得的肝脏样本，以确定患有更晚期肝病的患者是否有肝线粒体，在体外和离体，表现出较差的能量产生（质量控制）、生物发生和线粒体自噬； SA2将隔离 9个月后再次检测肝线粒体，以测试 IHTG 的丧失是否与改善通过基因表达、酶水平评估线粒体功能、生物发生和质量控制和脂肪酸氧化。 SA3 将测量受试者的全身葡萄糖和脂肪酸通量 - 进行积极治疗（CR+EX）和标准护理。将在基线和 9 点之后采取措施月，并使用数学模型来量化外围营养物的处置和减少肝脏营养负担，以比较其对线粒体功能、纤维化的影响，并通过活检使用组织学评估确定 NASH 活动评分。总之，这些研究将通过以下发现显着推进了 NAFLD 领域的发展：1) 过量的机制营养应激导致肝线粒体功能降低，2) 之间的关系线粒体活性和 NASH 的组织学特征。重要的是，这项工作将发挥持续的作用通过确定人类肝线粒体功能障碍是否可逆来对该领域产生影响。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Hepatocyte-specific eNOS deletion impairs exercise-induced adaptations in hepatic mitochondrial function and autophagy.

DOI：
10.1002/oby.23414
发表时间：
2022-05
期刊：
Obesity (Silver Spring, Md.)
影响因子：
0
作者：
通讯作者：

The Utility and Diagnostic Accuracy of Transient Elastography in Adults with Morbid Obesity: A Prospective Study.

DOI：
10.3390/jcm11051201
发表时间：
2022-02-23
期刊：
Journal of clinical medicine
影响因子：
3.9
作者：
Ali AH;Al Juboori A;Petroski GF;Diaz-Arias AA;Syed-Abdul MM;Wheeler AA;Ganga RR;Pitt JB;Spencer NM;Hammoud GM;Rector RS;Parks EJ;Ibdah JA
通讯作者：
Ibdah JA

Compromised hepatic mitochondrial fatty acid oxidation and reduced markers of mitochondrial turnover in human NAFLD.

DOI：
10.1002/hep.32324
发表时间：
2022-11
期刊：
HEPATOLOGY
影响因子：
13.5
作者：
Moore, Mary P.;Cunningham, Rory P.;Meers, Grace M.;Johnson, Sarah A.;Wheeler, Andrew A.;Ganga, Rama R.;Spencer, Nicole M.;Pitt, James B.;Diaz-Arias, Alberto;Swi, Ahmed I. A.;Hammoud, Ghassan M.;Ibdah, Jamal A.;Parks, Elizabeth J.;Rector, R. Scott
通讯作者：
Rector, R. Scott

A Model Incorporating Serum Alkaline Phosphatase for Prediction of Liver Fibrosis in Adults with Obesity and Nonalcoholic Fatty Liver Disease.

DOI：
10.3390/jcm10153311
发表时间：
2021-07-27
期刊：
Journal of clinical medicine
影响因子：
3.9
作者：
Ali AH;Petroski GF;Diaz-Arias AA;Al Juboori A;Wheeler AA;Ganga RR;Pitt JB;Spencer NM;Hammoud GM;Rector RS;Parks EJ;Ibdah JA
通讯作者：
Ibdah JA

A Fad too Far? Dietary Strategies for the Prevention and Treatment of NAFLD.