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Regulation of Hepatic Macronutrient Metabolism by Mitochondrial Citrate Transport

线粒体柠檬酸盐转运对肝脏大量营养素代谢的调节

基本信息

批准号：
10058737
负责人：
Eric B Taylor
金额：
$ 44.26万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10058737
关键词：
Acetates Address Attenuated Automobile Driving Carbon Chronic Citrate (si)-Synthase Citrates Cytosol Data Diet Disease Progression Enzymes Fatty Liver Fatty acid glycerol esters Functional disorder Generations Gluconeogenesis Glucose Glucose Intolerance Glycolysis Goals Health Hepatic Hyperglycemia Insulin Resistance Investigation Knock-out Knowledge Link Lipids Liver Liver Mitochondria Macronutrients Nutrition Mediating Metabolic Metabolism Mission Mitochondria Modeling Mus NADP Non-Insulin-Dependent Diabetes Mellitus Pharmacology Public Health Reaction Regulation Research Role Somatotype Source Sucrose Testing Therapeutic Time United States National Institutes of Health citrate carrier experimental study feeding glucose metabolism in vivo in vivo evaluation innovation insulin sensitivity lipid biosynthesis liver metabolism metabolomics mitochondrial metabolism non-alcoholic fatty liver disease novel

项目摘要

PROJECT SUMMARY During type 2 diabetes (T2D), loss of insulin sensitivity strongly associated with hepatic lipid accumulation increases gluconeogenesis underlying chronic hyperglycemia. Furthermore, increased hepatic de novo lipogenesis (DNL) during T2D is thought to drive insulin resistance and non-alcoholic fatty liver disease (NAFLD). Thus, identifying mechanisms directly modulating both hepatic DNL and gluconeogenesis could be uniquely valuable for understanding T2D pathophysiology and therapeutic opportunity. Cytosolic citrate is believed to be a master regulator of hepatic metabolism by reciprocally regulating glycolysis and gluconeogenesis and by supplying substrate and reducing power for DNL. Citrate is produced in the mitochondria and requires a specific transporter, the mitochondrial citrate carrier (CiC), to reach the cytosol. Thus, the CiC is predicted to occupy a central metabolic node linking hepatic mitochondrial metabolism, DNL, glucose, and reductive drive. Yet, surprisingly, the role of the CiC modulating hepatic DNL and gluconeogenesis in normal and T2D states remains sparsely addressed in vivo. The overall goal of this application is to understand how the hepatic CiC contributes to fundamental metabolism and T2D pathophysiology. This will be addressed by pursuing two specific aims: 1) Determine how hepatic CiC function regulates hepatic DNL in T2D states; and 2) Determine how hepatic CiC function contributes to hyperglycemia in T2D states. Experiments in aim 1 will test the hypothesis that disrupting hepatic CiC activity in vivo during T2D states decreases DNL, by decreasing supply of citrate as a carbon source and decreasing NAPDH available for fatty chain elongation. Experiments in aim 2 will test the hypothesis that disrupting hepatic CiC activity in vivo during T2D states decreases hyperglycemia by attenuating liver insulin resistance, shifting hepatic glucose metabolism towards glycolysis away from gluconeogenesis, and decreasing mouse correlates of NAFLD progression. Overall, the proposed investigation will test the fundamental regulatory role of the CiC in vivo and provide novel, mechanistic information on how the single metabolic step of mitochondrial citrate export contributes to the core T2D features of increased hepatic DNL and gluconeogenesis. This research is significant because successful completion will uniquely advance fundamental understanding of T2D pathophysiology. This research is innovative because it will utilize novel in vivo CiC disruption and metabolomic tracing models to test the role of the CiC role linking mitochondrial metabolism, DNL, and gluconeogenesis in T2D.

项目总结