Alcohol and calorie-dense diet-mediated hepatic mitochondrial dysregulation

酒精和高热量饮食介导的肝线粒体失调

基本信息

批准号：
10679945
负责人：
Eden McMillin Gallegos
金额：
$ 3.95万
依托单位：
LSU HEALTH SCIENCES CENTER
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：
2023-04-17 至 2028-04-16
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10679945
关键词：
Alcohol consumption Alcoholic Hepatitis Alcoholic Liver Diseases Alcoholic beverage heavy drinker Alcohols Antioxidants Bioenergetics Biogenesis Biological Assay Calories Cell Culture Techniques Cells Cellular Structures Characteristics Cholesterol Chronic Cirrhosis Citric Acid Cycle Coin Consensus Consumption Data Dedications Development Diet Disease Ensure Environment Ethanol Fatty Liver Fatty acid glycerol esters Fellowship Fostering Functional disorder Future Gene Expression Genes Genus Hippocampus Goals HIV Health Health Sciences Hepatic Hepatocyte High Fat Diet Histology Immune Immunofluorescence Immunologic In Vitro Incidence International Laboratories Learning Lipids Literature Liver Liver Mitochondria Louisiana Macaca Mediating Medical Medicine Mentors Metabolic Metabolic Diseases Mitochondria Mitochondrial DNA Modeling National Research Service Awards Non-Insulin-Dependent Diabetes Mellitus Nutrient Obesity Organ Organelles Overweight Oxidative Phosphorylation Palmitic Acids Patients Peroxisome Proliferator-Activated Receptors Persons Physicians Primary carcinoma of the liver cells Process Production Publishing Reactive Oxygen Species Research Research Personnel Risk Rodent Model SIV Scientist Skeletal Muscle Stress Tests Sucrose Technology Testing Training Transplantation Surgery Triglycerides UCP2 protein Universities Western Blotting Work alcohol effect alcohol measurement alcohol response alcohol risk biobank career career development cell injury clinically relevant dietary control drinking fatty liver disease improved in vitro Model insight interest lentivirally transduced liver biopsy liver injury liver transplantation metabolic-associated fatty liver disease non-alcoholic fatty liver disease organ injury overexpression oxidation pre-clinical pre-clinical research receptor saturated fat success sugar training opportunity translational study translational therapeutics

项目摘要

1 Abstract 2 The goal of this Ruth L. Kirschstein 3 career. The applicant’s career development will come in large part from work in hepatic models of alcohol, high 4 fat, and high sucrose exposure. The applicant will have the invaluable opportunity to conduct high quality 5 research using a well-established preclinical macaque model of chronic binge alcohol (CBA) administration and 6 an in vitro HepaRG spheroid cell culture model of hepatocytes. Alcohol-related liver injury is a leading cause of 7 end-organ disease, and the combined impact of alcohol and a calorie-dense diet on liver pathophysiology has 8 yet to be well characterized. Several studies of either alcohol- or high fat diet-related liver injuries demonstrate 9 that mitochondrial oxidative phosphorylation (OXPHOS) and remodeling (biogenesis and dynamics) are 10 decreased or disrupted in response to alcohol or high fat. Data from the laboratory showed CBA-mediated 11 decreased hepatic expression of genes involved in mitochondrial biogenesis, OXPHOS, and fusion such as 12 peroxisome proliferator-activated receptor-g coactivator-1b (PGC-1b) and mitofusin-2 (MFN2) in control diet-fed 13 macaques. Additionally, preliminary data generated for this proposal from liver biopsies of short-term high fat, 14 high sucrose (HFS) diet (HFSD) fed macaques showed increased expression of genes involved in lipid 15 accumulation. Previous work from the laboratory demonstrated that alcohol dysregulates mitochondrial 16 remodeling and bioenergetics in skeletal muscle and immune cells. Taken together, preliminary data and 17 published literature provide evidence of alcohol-mediated mitochondrial adaptations leading to end-organ injury. 18 Thus, the hypothesis of the proposed project is that alcohol and HFSD together disrupt mitochondrial remodeling, 19 decrease OXPHOS, and increase lipid accumulation in the liver, and that promoting PGC-1b expression 20 ameliorates these changes in hepatocytes. Using livers from CBA or vehicle administered HFSD-fed macaques 21 at multiple timepoints and an in vitro model of alcohol and HFS-treated hepatocytes, the applicant aims to test 22 that alcohol and HFS disrupt hepatic mitochondrial remodeling, decrease hepatic OXPHOS, and increase 23 hepatic lipid accumulation. Further, whether or not promoting hepatocyte PGC-1b expression will ameliorate 24 these alcohol and HFS-mediated alterations will be determined. Findings from the proposed studies will provide 25 insight into metabolic dysregulation caused by alcohol in the context of HFSD. Additionally, the project aims to 26 show that PGC-1b overexpression increases mitochondrial biogenesis, fusion, and OXPHOS and has the 27 potential to improve liver health in alcohol- and HFSD-induced liver injury. With a strong mentoring team 28 dedicated to developing a well-rounded physician scientist, completion of the proposed training plan in alcohol 29 abuse-related research will ensure that the applicant is equipped for a successful career in academic medicine. NRSA F30 application is to prepare the applicant for an academic medical

1 摘要 2 Ruth L. Kirschstein 的目标 3. 申请人的职业发展很大程度上来自于酒精、高浓度肝模型的工作。 4. 脂肪和高蔗糖暴露申请人将有进行高质量的宝贵机会。 5 使用成熟的临床前猕猴慢性酗酒 (CBA) 模型进行的研究图6 肝细胞的体外HepaRG球状细胞培养模型酒精相关的肝损伤是导致肝细胞损伤的主要原因。 7 终末器官疾病，以及酒精和高热量饮食对肝脏病理生理学的综合影响 8 多项关于酒精或高脂肪饮食相关肝损伤的研究尚未得到充分表征。 9 线粒体氧化磷酸化 (OXPHOS) 和重塑（生物发生和动力学） 10 对酒精或高脂肪的反应减少或中断。实验室数据显示 CBA 介导。 11 参与线粒体生物合成、OXPHOS 和融合的基因的肝脏表达减少，例如 12 饮食喂养对照中的过氧化物酶体增殖物激活受体-g 共激活剂-1b (PGC-1b) 和线粒体融合蛋白-2 (MFN2) 13 只猕猴还通过短期高脂肪肝活检获得了初步数据。 14只高蔗糖（HFS）饮食（HFSD）喂养的猕猴表现出与脂质相关的基因表达增加 15 实验室先前的研究表明，酒精会导致线粒体失调。 16 骨骼肌和免疫细胞的重塑和生物能学综合起来，初步数据和 17 篇发表的文献提供了酒精介导的线粒体适应导致终末器官损伤的证据。 18 因此，该项目的假设是酒精和 HFSD 一起破坏线粒体重塑， 19 减少 OXPHOS，增加肝脏脂质积累，促进 PGC-1b 表达 20 使用来自 CBA 或给予 HFSD 喂养的猕猴的载体改善了肝细胞的这些变化。 21 在多个时间点以及酒精和 HFS 处理的肝细胞的体外模型中，申请人旨在测试 22 酒精和 HFS 会破坏肝线粒体重塑，降低肝 OXPHOS，并增加 23. 进一步，促进肝细胞PGC-1b表达是否会改善。 24 这些酒精和 HFS 介导的改变将由拟议研究的结果确定。 25 深入了解 HFSD 背景下酒精引起的代谢失调。图 26 显示 PGC-1b 过表达增加线粒体生物合成、融合和 OXPHOS，并具有 27 拥有强大的指导团队，可改善酒精和 HFSD 引起的肝损伤的肝脏健康。 28 致力于培养全面发展的医师科学家，完成拟议的酒精培训计划 29 与滥用相关的研究将确保申请人具备在学术医学领域取得成功职业生涯的能力。 NRSA F30 申请旨在帮助申请人为学术医疗做好准备