The Effects of Acetate on Brain

NIDA的Nora Volkow博士观察到，酒精摄入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。李天凯博士指出，葡萄糖利用率的下降可以用乙酸盐的大脑代谢来解释，在乙醇代谢过程中，乙酸盐的血液水平达到2 mM。在乔治·库诺斯博士和生理研究实验室成员的合作下，我们确定，当血液中醋酸盐浓度升高到5或2 mM时，大脑对F-葡萄糖的摄取显著减少，醋酸盐进入大脑的Km约为5 mm。简单地测量葡萄糖利用率的降低，很少有关于从葡萄糖代谢转换为醋酸盐代谢对大脑能量、神经递质、转录或神经肽代谢的影响的信息。 尽管多年来，NIAAA等人对乙醇对大脑和肝脏功能的影响进行了广泛的研究，但对于乙酸盐对大脑能量代谢的影响，关注相对较少。线粒体通透性转换孔的打开，破坏了ATP合成所依赖的质子梯度。因此，它本质上是呼吸链中电子运输与ATP合成的解偶联，本质上是作为解偶联剂，如FCCP。长时间打开毛孔允许更大的分子，如细胞色素C，从线粒体进入细胞质，触发细胞凋亡过程。 在我们的研究中，我们发现，给大鼠注射乙醇或醋酸盐，会导致大脑对葡萄糖的磷酸化减少。我们还发现，服用醋酸盐会导致ATP水解的增量G‘降低。 我们现在发现，脑内醋酸盐的代谢引起了脑生理的显著变化，即葡萄糖磷酸化减少，ATP水解量G‘降低，线粒体NAD和Q对氧化，胞浆NAD对减少，氧化磷酸化解偶联。由于大脑生理学上的深刻变化，有必要进一步研究在正常酒精消费过程中必须引起这些变化的条件。

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.