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：
10412049
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 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10412049
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.

项目摘要在2型糖尿病（T2D）期间，与肝脂质积累密切相关的胰岛素敏感性的丧失会增加慢性高血糖的基础糖生成。此外，T2D期间肝脂肪生成（DNL）的增加被认为促进胰岛素抵抗和非酒精性脂肪肝病（NAFLD）。因此，识别直接调节肝DNL和糖异生的机制对于理解T2D病理生理学和治疗机会可能是独特的。据信，通过互惠调节糖酵解和糖异生，并通过提供底物和降低DNL的能力，可以通过相互调节的糖酵解和葡萄糖生成来成为肝代谢的主要调节剂。柠檬酸盐是在线粒体中产生的，需要特定的转运蛋白，即线粒体柠檬酸盐载体（CIC）才能到达胞质溶胶。因此，预测CIC将占据中央代谢淋巴结，将肝线粒体代谢，DNL，葡萄糖和还原性驱动连接。然而，令人惊讶的是，在正常和T2D状态下，CIC调节肝DNL和糖异生的作用在体内仍然稀少。该应用的总体目标是了解肝CIC如何促进基本代谢和T2D病理生理学。这将通过追求两个具体目标来解决：1）确定肝CIC功能如何调节T2D州的肝DNL； 2）确定肝CIC功能如何在T2D状态下有助于高血糖。 AIM 1中的实验将检验以下假设：T2D状态期间肝CIC活性破坏了DNL，通过减少柠檬酸盐作为碳源的供应并降低可用于脂肪链延长的NAPDH，从而降低了DNL。 AIM 2中的实验将检验以下假设：T2D状态期间的肝CIC活性破坏了体内的肝CIC活性，通过减轻肝胰岛素抵抗，转移肝葡萄糖代谢向糖酵解转移到葡萄糖生成上，从而降低高血糖，并降低糖酵解的糖酵解，并降低小鼠进展的小鼠相关。总体而言，拟议的研究将测试CIC在体内的基本调节作用，并提供有关线粒体柠檬酸盐的单个代谢步骤如何有助于增加肝DNL和糖原发生的核心T2D特征。这项研究很重要，因为成功完成将独特地提高对T2D病理生理学的基本理解。这项研究具有创新性，因为它将利用新颖的体内CIC破坏和代谢组学模型来测试CIC在T2D中连接线粒体代谢，DNL和糖异生的作用。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

3-hydroxykynurenine is a ROS-inducing cytotoxic tryptophan metabolite that disrupts the TCA cycle.

3-羟基犬尿氨酸是一种 ROS 诱导细胞毒性色氨酸代谢物，可破坏 TCA 循环。

DOI：
10.1101/2023.07.10.548411
发表时间：
2023
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Buchanan,JaneL;Rauckhorst,AdamJ;Taylor,EricB
通讯作者：
Taylor,EricB

Mild Impairment of Mitochondrial OXPHOS Promotes Fatty Acid Utilization in POMC Neurons and Improves Glucose Homeostasis in Obesity.

DOI：
10.1016/j.celrep.2018.09.034
发表时间：
2018-10-09
期刊：
Cell reports
影响因子：
8.8
作者：
Timper K;Paeger L;Sánchez-Lasheras C;Varela L;Jais A;Nolte H;Vogt MC;Hausen AC;Heilinger C;Evers N;Pospisilik JA;Penninger JM;Taylor EB;Horvath TL;Kloppenburg P;Brüning JC
通讯作者：
Brüning JC

Mitochondrial citrate metabolism and efflux regulates trophoblast differentiation.

线粒体柠檬酸盐代谢和流出调节滋养层分化。

DOI：
10.1101/2023.01.22.525071
发表时间：
2023
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Mahr,ReneeM;Jena,Snehalata;Nashif,SereenK;Nelson,AlisaB;Rauckhorst,AdamJ;Rome,FerrolI;Sheldon,RyanD;Hughey,CurtisC;Puchalska,Patrycja;Gearhart,MicahD;Taylor,EricB;Crawford,PeterA;Wernimont,SarahA
通讯作者：
Wernimont,SarahA

Isolated Effects of Plasma Freezing versus Thawing on Metabolite Stability.