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

• 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
• 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

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)抽象