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The Role of Mitochondrial Dysfunction in Non-Alcoholic Fatty Liver Disease

线粒体功能障碍在非酒精性脂肪肝中的作用

基本信息

批准号：
8401182
负责人：
JEFFREY D BROWNING
金额：
$ 44.29万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-02-23 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8401182
关键词：
Acetoacetates Affect Alanine Benign Biological Assay Carnitine Cell physiology Cirrhosis Citrates Citric Acid Cycle Clinical Data Development Diabetes Mellitus Disease Effectiveness Fasting Fatty Acids Fatty acid glycerol esters Fingerprint Generations Gluconeogenesis Glucose Goals Grant Hepatic Hepatocyte Histologic Human Hydroxybutyrates Impairment Individual Inflammation Insulin Resistance Ketones Lead Link Liver Liver Mitochondria Liver diseases Malonyl Coenzyme A Mass Spectrum Analysis Measurement Measures Metabolic Metabolism Metformin Methodology Methods Mitochondria NMR Spectroscopy Nuclear Magnetic Resonance Obesity Oxidation-Reduction Oxidative Phosphorylation Oxidative Stress Pathogenesis Patients Peripheral Pharmaceutical Preparations Population Process Production Propionates Rattus Reaction Reporting Research Risk Rodent Role Skeletal Muscle Staging Steatohepatitis Techniques Testing Time Tissues Tracer Transferase Triglycerides attenuation base clinical care fatty acid oxidation glucose metabolism glucose production glycogenolysis improved in vivo insight ketogenesis liver biopsy mitochondrial dysfunction non-alcoholic fatty liver nonalcoholic steatohepatitis oxidation public health relevance radiotracer response stable isotope

项目摘要

DESCRIPTION (provided by applicant): Mitochondrial dysfunction may be responsible for the pathogenesis and progression of non-alcoholic fatty liver disease (NAFLD), a condition that affects over 71 million individuals in the U.S. alone. Impaired mitochondrial function could lead to both the initial accumulation of hepatic triglycerides via decreased oxidative disposal, as well as the transition to steatohepatitis due to enhanced oxidative stress originating from the plethora of redox reactions required for oxidative phosphorylation. As a result, we believe that there may be significant differences in mitochondrial metabolism between individuals with bland steatosis, presumed to be a benign condition, and steatohepatitis (NASH), a progressive and morbid form of NAFLD. The goal of this grant will be to use newly-developed, non-invasive, in vivo NMR-based stable isotope methodologies to define the role of hepatic mitochondrial dysfunction in the development of NAFLD and how these alterations relate to the development of insulin resistance and NASH. Such measurements are difficult or impossible to do using standard mass spectrometry techniques or classic radiotracers. The first aim of this proposal seeks to determine if the increased rates of gluconeogenesis observed in insulin resistance and NAFLD are associated with increased energy generation via the citric acid (TCA) cycle, a component of mitochondrial function. We have observed an association between energy generation in the TCA cycle and gluconeogenesis occurring from precursors such as lactate and alanine, suggesting that these processes are energetically linked. In the second aim of this proposal we will determine if progression from bland steatosis to NASH is associated with a progressive decline in a second component of mitochondrial function, ketogenesis. Several reports demonstrate that FA synthesis in liver is inappropriately increased in subjects with NAFLD, implying that mitochondrial FA 2-oxidation is inhibited via the effect of malonyl-CoA on carnitine palmitoyl transferase. Attenuation of hepatic 2-oxidation may be associated with decreased export of ketones to the periphery in favor of local energy generation to support cellular processes in the hepatocyte. In the final aim, the ability of metformin, a proposed therapy for NAFLD, to augment hepatic mitochondrial function in individuals with NAFLD will be quantified. The benefits of the proposed research are several-fold: First, improved understanding of the metabolic derangements complicit in the pathogenesis and progression of NAFLD will allow better clinical insight and focused approaches to therapy; Second, our methodologies may provide a simple, non-invasive method to identify individuals with NASH, who are at greatest risk of progressive liver disease; and Third, a better understanding of the mechanism of action of metformin in the treatment of NAFLD will allow this therapy to be targeted to individuals most likely to derive benefit.

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