The Effects of Acetate on Brain

醋酸盐对大脑的影响

• 批准号: 8344668
• 负责人: richard l veech
• 金额: $ 71.18万
• 依托单位: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8344668
• 关键词: ATP Hydrolysis; ATP Synthesis Pathway; Acetate-CoA Ligase; Acetates; Acetyl Coenzyme A; Alcohol consumption; Apoptosis; Attention; Blood; Brain; Citric Acid Cycle; Coenzyme A; Collaborations; Couples; Cyclic AMP; Cytochromes; Cytoplasm; Diphosphates; Electron Transport; Electrons; Energy Metabolism; Ethanol; Ethanol Metabolism; Extrahepatic; Genetic Transcription; Glucose; Heart; Heating; Hormones; Kidney; Lead; Liver; Measurement; Measures; Metabolic; Metabolism; Mitochondria; Mitochondrial Matrix; Movement; Muscle; National Institute of Drug Abuse; National Institute on Alcohol Abuse and Alcoholism; Neuropeptides; Neurotransmitters; Oxidative Phosphorylation; Pattern; Pennsylvania; Permeability; Phosphorylation; Physiological; Physiology; Portal vein structure; Process; Protons; Rattus; Reaction; Respiratory Chain; System; Thermogenesis; Uncoupling Agents; Universities; alcohol effect; brain metabolism; glucose metabolism; lead acetate; liver function; member; mitochondrial permeability transition pore; oxidation; problem drinker; uptake; voltage

Dr. Nora Volkow, of NIDA, observed that alcohol consumption decreased brain glucose utilization in alcoholic subjects in a pattern which resemble GABAergic stimulation. Dr. T-K Li pointed out that the decrease in glucose utilization could be explained by the brain metabolism of acetate, which reaches blood levels of 2 mM during ethanol metabolism. In collaboration with Dr. George Kunos and members of the Lab of Physiological Studies, we determined that brain uptake of F dexoyglucose was significantly decreased by elevation of blood acetate to 5 or 2 mM acetate, the Km for acetate transport into brain being about 5 mM. Simple measurement of a decreased rate of glucose utilization provides little information on the effects of switching from glucose to acetate metabolism on brain energetics, neurotransmitter, transcription or neuropeptide metabolism. While the effects of ethanol on brain and liver function have been extensively studied by the NIAAA and others for many years, there has been relatively little attention paid to the effects of acetate on the energy metabolism in brain. Opening of the mitochondrial permeability transition pore, destroys the proton gradient upon which the synthesis of ATP depends. It therefore is essentially uncoupling of the transport to electrons in the respiratory chain from the synthesis of ATP, in essence acting as an uncoupling agent such as FCCP. Prolonged opening of the pore allows for movement of larger molecules such as cytochrome C out of mitochondria into cytoplasm triggering the process of apoptosis. In our studies, we found that the administration of ethanol or acetate to the rat, led to a decrease in the phosphorylation of glucose by brain. We also found that administration of acetate lead to a decrease in the delta G' of ATP hydrolysis. We have now shown that the metabolism of acetate by brain causes significant changes in brain physiology, namely a decrease in glucose phosphorylation, a decrease in the delta G' of ATP hydrolysis, oxidation of the mitochondrial NAD and Q couples, reduction of the cytosolic NAD couple indicative of uncoupling of oxidation phosphorylation. Because of the profound changes on brain physiology, a further study of the conditions which must pertain to cause these changes in the course of normal ethanol consumption is warranted. It is proposed that this phenomena be explored further in a collaborative study with Prof Britton Chance of the University of Pennsylvania, where the amount of heat produced by the opening to the mitochondrial voltage dependent pore is measured after opening by acetate.

NIDA的Nora Volkow博士观察到，酒精消耗以类似于GABA能刺激的模式降低了酒精受试者的脑葡萄糖利用。 T-K Li博士指出，葡萄糖利用率的降低可以通过乙酸的脑代谢来解释，乙酸的脑代谢达到乙醇代谢期间的血液水平为2 mM。与乔治·库诺斯（George Kunos）博士和生理学研究实验室成员合作，我们确定脑摄取F乙酸乙酸乙酯的脑部吸收显着降低，乙酸血液升高到乙酸5或2 mm乙酸盐，乙酸乙酸盐的乙酸盐将乙酸盐转运到大脑约为5 mm。降低葡萄糖利用率的简单测量几乎没有关于从葡萄糖转换为乙酸代谢对脑能量，神经递质，转录或神经肽代谢的影响的信息。 尽管NIAAA和其他其他人已经对乙醇对脑和肝功能的影响进行了多年的广泛研究，但对乙酸盐对大脑能量代谢的影响的关注相对较少。 线粒体通透性过渡孔的打开，破坏了ATP合成所取决于的质子梯度。 因此，它本质上是从ATP的合成中将呼吸链中电子传输的耦合，从本质上讲，它是诸如FCCP之类的解偶联剂。 孔的长时间打开可以使较大的分子从线粒体中移动到细胞质中，从而触发凋亡过程。 在我们的研究中，我们发现乙醇或乙酸对大鼠的施用导致大脑葡萄糖磷酸化的降低。 我们还发现，乙酸盐的给药会导致ATP水解的三角肌减少。 现在，我们已经表明，乙酸盐的代谢会导致脑生理学的显着变化，即葡萄糖磷酸化的降低，ATP水解的三角肌的降低，线粒体NAD的氧化和Q的氧化，Q coupers的氧化，氧化无良的NAD夫妇的降低，表明了氧化的氧化作用。 由于脑生理的深刻变化，必须对在正常乙醇消耗过程中必须导致这些变化的状况进行进一步的研究。 建议在与宾夕法尼亚大学的布里顿教授的一项合作研究中进一步探讨这种现象，在那里，通过乙酸盐开放后测量了对线粒体电压依赖性孔产生的热量。

项目成果

Alterations in brain glucose utilization accompanying elevations in blood ethanol and acetate concentrations in the rat.

• DOI: 10.1111/j.1530-0277.2009.01099.x
• 发表时间: 2010-02
• 期刊: Alcoholism, clinical and experimental research
• 作者: Pawlosky RJ;Kashiwaya Y;Srivastava S;King MT;Crutchfield C;Volkow N;Kunos G;Li TK;Veech RL
• 通讯作者: Veech RL