| Research Abstract |
Acetoacetyl-CoA(AA-CoA) synthetase (acetoacetyl-CoA ligase, EC 6.2.1.16) is a novel cytosolic acetoacetate-activating enzyme pulified as the acetoacetyl-specific ligase. In mammals, AA-CoA synthetase is present in liver, brain, adipose tissues and other various tissues, and this enzyme was highly expressed in rat and human brain. In the liver, AA-CoA synthetase is considered to be related cholesterol biosynthesis and fatty acid synthesis. However, except in the liver, the physiological role of AA-CoA synthetase is not clear yet. In order to clarify the physiological role of AA-CoA synthetase in the brain, (1)distribution of AA-CoA synthetase protein and mRNA in various regions of rat brain, (2)localization of AA-CoA synthetase mRNA in the brain by in situ hybridization, (3)comparison between AA-CoA synthetase mRNA distribution and other lipid synthesis enzymes' in the brain, and (4)effect of streptozotocin(STZ)-induced diabetes on the AA-CoA synthetase and various enzymes. First, AA-Co
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A synthetase mRNA and protein were widely expressed in rat brain, and these expression were particularly high in pons, medulla oblongata, midbrain, cerebral cortex and hypothalamus. Furthermore, the localization of AA-CoA synthetase mRNA in rat brain slices was found to be especially high in cerebellum white matter, hippocampus cornu ammonis and dentate gyrus. In the cerebral cortex including hippocampus, the hybridization signals are apt to express in neurocyte. The expression of the enzyme was high in neurocyte of the regions suggest that this enzyme may have the important role in memory and learning function. Furthermore, expression pattern of the AA-CoA synthetase mRNA was also similar to that of HMG-CoA reductase (the rate-determining enzyme of cholesterol biosynthesis) and not similar to that of Succinyl-CoA transferase (mitochondrial ketone body metabolic enzyme). These results suggest that AA-CoA synthetase is involved in the roles of cholesterol biosynthesis than the generation of metabolic energy in the brain. Next, in order to investigate the participation of insulin-depleted diabetes on AA-CoA synthetase, effect of streptozotocin administration on expression of this enzyme mRNA was examined in rat brain, heart, kidney and liver. As a result, STZ-induced diabetic rats showed markedly decreased AA-CoA synthetase mRNA expression in all tissues compared with normal control rats. Furthermore, compared effect of streptozotocin-induced diabetes on the AA-CoA synthetase mRNA with lipid synthesis and ketone body metabolic enzymes' in the brain because insulin has also been known to be important for lipogenic enzyme expression. Diabetic rats were markedly decreased AA-CoA synthetase, HMG-CoA reductase, Acetyl-CoA carboxylase mRNA expression but was hardly change Succinyl-CoA transferase mRNA. These results suggest that AA-CoA synthetase expression is regulated by insulin similarly lipid systhesis enzyme. In conclusion, AA-CoA synthetase is likely to play an important role in memory and learning function through ketone body metabolism for synthesis of cholesterol in the brain. Less
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