The Effects of Acetate on Brain

NIDA的诺拉罗博士观察到，酒精消耗降低了酒精受试者的大脑葡萄糖利用率，其模式类似于GABA能刺激。T-K Li博士指出，葡萄糖利用率的降低可以通过乙酸盐的脑代谢来解释，乙酸盐在乙醇代谢期间达到2 mM的血液水平。在与乔治库诺斯博士和生理研究实验室成员的合作中，我们确定，血液乙酸盐升高至5或2 mM乙酸盐时，大脑对F-脱氧葡萄糖的摄取显著降低，乙酸盐转运到脑中的Km约为5 mM。简单测量葡萄糖利用率的降低几乎不能提供关于从葡萄糖代谢转换为乙酸盐代谢对脑的影响的信息能量学、神经递质、转录或神经肽代谢。 虽然乙醇对大脑和肝脏功能的影响已经被NIAAA和其他人广泛研究了多年，但对乙酸盐对大脑能量代谢的影响关注相对较少。 线粒体渗透性转换孔的打开破坏了ATP合成所依赖的质子梯度。 因此，它本质上是从ATP合成中解偶联到呼吸链中的电子的转运，本质上充当解偶联剂，如FCCP。 孔的长时间打开允许较大的分子如细胞色素C从线粒体移动到细胞质中，触发细胞凋亡过程。 在我们的研究中，我们发现给大鼠注射乙醇或乙酸盐，导致大脑葡萄糖磷酸化的减少。 我们还发现给予乙酸盐导致ATP水解的Δ G'降低。 我们现在已经表明，脑对乙酸盐的代谢引起脑生理学的显著变化，即葡萄糖磷酸化的减少、ATP水解的Δ G'的减少、线粒体NAD和Q对的氧化、细胞溶质NAD对的减少指示氧化磷酸化的解偶联。 由于大脑生理学的深刻变化，有必要进一步研究在正常乙醇消耗过程中引起这些变化的条件。 有人提出，这种现象将进一步探讨在一项合作研究与宾夕法尼亚大学的教授布里顿机会，其中的热量所产生的线粒体电压依赖性孔的开放后，由醋酸盐开放测量。

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.