β‐Hydroxybutyrate as a Precursor to the Acetyl Moiety of Acetylcholine

Abstract

Rat brain cortex slices were incubated with 10 mM-glucose and trace amounts of [6-3H]glucose and [3-14C]beta-hydroxybutyrate. The effects of (-)-hydroxycitrate, an inhibitor of ATP-citrate lyase; methylmalonate, an inhibitor of beta-hydroxybutyrate dehydrogenase; and increasing concentrations of unlabeled acetoacetate were examined. The incorporation of label into lactate, citrate, malate, and acetylcholine (ACh) was measured and 3H:14C ratios calculated. Incorporation of [14C]beta-hydroxybutyrate into lactate was limited because of the low activity of gluconeogenic enzymes in brain, whereas incorporation of 14C label into Krebs cycle intermediates and ACh was higher than in previous experiments with [3H-,14C]-glucose. (-)-Hydroxycitrate (5.0 mM) reduced incorporation of [3H]glucose and [14C]beta-hydroxybutyrate into ACh. In contrast, slices incubated with methylmalonate (1 mM) showed a decrease in 14C incorporation without appreciably affecting glucose metabolism. The effects of high concentrations of methylmalonate were nonselective and yielded a generalized decrease in metabolism. Acetoacetate (1 mM) also produced a decreased 14C incorporation into ACh and its precursors. At 10 mM, acetoacetate reduced 3H and 14C incorporation into ACh without substantially affecting total ACh content. From the results, it is suggested that in adult rats beta-hydroxybutyrate can contribute to the acetyl moiety of ACh, possibly via the citrate cleavage pathway, though it is quantitatively less important than glucose and pyruvate. This contribution of ketone bodies could become significant should their concentration become abnormally high or glucose metabolism be reduced.

Effect of Chronic Lead Ingestion by Rats on Glucose Metabolism and Acetylcholine Synthesis in Cerebral Cortex Slices

“…1936;Browning and Shulman, 1968;Tutek and Cheng, 1974). cytosol and cleaved to AcCoA by ATP-citrate lyase (Sterling and O'Neill, 1978;Sterling et al, 1981). Several mechanisms for the transport of acetyl units across the mitochondrial membrane to the cytosol have been proposed (Jope, 1979;Doleial and Tutek, 1981;Tutek et al, 1981).…”

“…The effect of low dose chronic Pb2+ exposure on general metabolism and subsequent ACh synthesis in cerebral cortex slices was examined by using mixed-labeled substrates (See Sterling and O'Neill, 1978;Sterling et al, 1981 for details). The technique is based on the fact that one of the three hydrogens of the methyl group of acetyl-CoA is removed in its condensation with oxaloacetate in the formation of citrate, thereby lowering the "H/14C ratio in citrate to 0.67 (computed to a glucose ratio of I .OO).…”

“…cytosol and cleaved to AcCoA by ATP-citrate lyase (Sterling and O'Neill, 1978;Sterling et al, 1981). The conversion of tritium and I4C of [6-'HH, 6-'4C]glucose to ACh and metabolic intermediates in cerebral cortex slices is shown in Table 1A.…”

Compartmentation and regulation of acetylcholine synthesis at the synapse

“…Cholinergic neurons synthesize acetylcholine from choline and acetyl-CoA by means of the enzyme choline acetyltransferase (EC 2.3.1.6) located in the cytosolic compartment of the nerve ending (Tucek, 1978). Glucose and pyruvate are the main precursors of acetyl-CoA in adult mammalian brain (Browning & Shulman, 1968;see Clark et al, 1982, for review), although ketone bodies (3-hydroxybutyrate, acetoacetate) may also contribute in the neonatal brain (Gibson & Blass, 1979;Sterling et al, 1981). The precise mechanism whereby the acetyl moiety for acetylcholine synthesis is transported from the mitochondrial compartment to the cytosol is still unclear, given that the mitochondrial membrane is impermeable to acetyl-CoA.…”

Effect of Administration Method on Blood Garcinia cambogia Concentration and Antioxidative Activity

“…HCA는 (5,6). 또한 식욕 촉진과 관련된 신경전달 물질인 acetylcholine의 전구체인 acetyl-CoA의 합성을 저해함으로써 식욕 저하에 영향을 미치며, acetyl-CoA의 이용 제한으로 간에서의 글리코겐 합성이 증가되어 뇌 시상하부의 포만중 추를 자극하여 식욕이 억제될 수 있다고 알려져 있다 (7,8 (Fig. 4).…”