title: Roles and regulation of ketogenesis in cultured astroglia and neurons under hypoxia and hypoglycemia.
abstract: Exogenous ketone bodies (KBs), acetoacetate (AA), and β-hydroxybutyrate (BHB) act as alternative energy substrates in neural cells under starvation. The present study examined the endogenous ketogenic capacity of astroglia under hypoxia with/without glucose and the possible roles of KBs in neuronal energy metabolism. Cultured neurons and astroglia were prepared from Sprague-Dawley rats. Palmitic acid (PAL) and l-carnitine (LC) were added to the assay medium. The 4- to 24-hr production of AA and BHB was measured using the cyclic thio-NADH method. (14)C-labeled acid-soluble products (KBs) and (14)CO2 produced from [1-(14)C]PAL were also measured. l-[U-(14)C]lactic acid ([(14)C]LAC), [1-(14)C]pyruvic acid ([(14)C]PYR), or β-[1-(14)C]hydroxybutyric acid ([(14)C]BHB) was used to compare the oxidative metabolism of the glycolysis end products with that of the KBs. Some cells were placed in a hypoxic chamber (1% O2). PAL and LC induced a higher production of KBs in astroglia than in neurons, while the CO2 production from PAL was less than 5% of the KB production in both astroglia and neurons. KB production in astroglia was augmented by the AMP-activated protein kinase activators, AICAR and metformin, as well as hypoxia with/without glucose. Neuronal KB production increased under hypoxia in the absence of PAL and LC. In neurons, [(14)C]LAC and [(14)C]PYR oxidation decreased after 24 hr of hypoxia, while [(14)C]BHB oxidation was preserved. Astroglia responds to ischemia in vitro by enhancing KB production, and astroglia-produced KBs derived from fatty acid might serve as a neuronal energy substrate for the tricarboxylic acid cycle instead of lactate, as pyruvate dehydrogenase is susceptible to ischemia.
authors.affiliation: Department of Neurology, Keio University School of Medicine, Tokyo, Japan takashin@tka.att.ne.jp.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Takahashi
authors.affiliation: Department of Neurology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Iizumi
authors.affiliation: Department of Neurology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Mashima
authors.affiliation: Department of Neurology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Takato
authors.initials: T
authors.lastname: Abe
authors.affiliation: Department of Neurology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Norihiro
authors.initials: N
authors.lastname: Suzuki
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000494:pharmacology; D000090:Acetoacetates / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D002247:Carbon Isotopes / Q000378:metabolism; D002331:Carnitine / Q000378:metabolism / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004622:Embryo, Mammalian; D000860:Hypoxia / Q000378:metabolism*; D007657:Ketone Bodies / Q000378:metabolism* / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D019308:Palmitic Acid / Q000494:pharmacology; D030481:Pyruvate Dehydrogenase (Lipoamide); D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D000090:Acetoacetates; D002247:Carbon Isotopes; D007657:Ketone Bodies; D019308:Palmitic Acid; C016635:acetoacetic acid; D030481:Pyruvate Dehydrogenase (Lipoamide); D002331:Carnitine; D020155:3-Hydroxybutyric Acid
keywords: AMP-activated protein kinase; acetoacetate; ketone bodies; long-chain fatty acids; palmitic acid; β-hydroxybutyrate