title: Uptake and metabolism of fructose by rat neocortical cells in vivo and by isolated nerve terminals in vitro.
abstract: Fructose reacts spontaneously with proteins in the brain to form advanced glycation end products (AGE) that may elicit neuroinflammation and cause brain pathology, including Alzheimer's disease. We investigated whether fructose is eliminated by oxidative metabolism in neocortex. Injection of [(14) C]fructose or its AGE-prone metabolite [(14) C]glyceraldehyde into rat neocortex in vivo led to formation of (14) C-labeled alanine, glutamate, aspartate, GABA, and glutamine. In isolated neocortical nerve terminals, [(14) C]fructose-labeled glutamate, GABA, and aspartate, indicating uptake of fructose into nerve terminals and oxidative fructose metabolism in these structures. This was supported by high expression of hexokinase 1, which channels fructose into glycolysis, and whose activity was similar with fructose or glucose as substrates. By contrast, the fructose-specific ketohexokinase was weakly expressed. The fructose transporter Glut5 was expressed at only 4% of the level of neuronal glucose transporter Glut3, suggesting transport across plasma membranes of brain cells as the limiting factor in removal of extracellular fructose. The genes encoding aldose reductase and sorbitol dehydrogenase, enzymes of the polyol pathway that forms glucose from fructose, were expressed in rat neocortex. These results point to fructose being transported into neocortical cells, including nerve terminals, and that it is metabolized and thereby detoxified primarily through hexokinase activity. We asked how the brain handles fructose, which may react spontaneously with proteins to form 'advanced glycation end products' and trigger inflammation. Neocortical cells took up and metabolized extracellular fructose oxidatively in vivo, and isolated nerve terminals did so in vitro. The low expression of fructose transporter Glut5 limited uptake of extracellular fructose. Hexokinase was a main pathway for fructose metabolism, but ketohexokinase (which leads to glyceraldehyde formation) was expressed too. Neocortical cells also took up and metabolized glyceraldehyde oxidatively.
authors.affiliation: Department of Neurology, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Norwegian Defence Research Establishment, Kjeller, Norway.
authors.forename: Bjørnar
authors.initials: B
authors.lastname: Hassel
authors.forename: Ahmed
authors.initials: A
authors.lastname: Elsais
authors.forename: Anne-Sofie
authors.initials: AS
authors.lastname: Frøland
authors.forename: Erik
authors.initials: E
authors.lastname: Taubøll
authors.forename: Leif
authors.initials: L
authors.lastname: Gjerstad
authors.forename: Yi
authors.initials: Y
authors.lastname: Quan
authors.forename: Raymond
authors.initials: R
authors.lastname: Dingledine
authors.forename: Frode
authors.initials: F
authors.lastname: Rise
mesh_terms: D027322:Amino Acid Transport System X-AG / Q000235:genetics / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D002247:Carbon Isotopes / Q000378:metabolism; D005631:Fructokinases; D005632:Fructose / Q000378:metabolism*; D005634:Fructose-Bisphosphate Aldolase / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D005985:Glyceraldehyde / Q000378:metabolism; D006593:Hexokinase / Q000378:metabolism; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D053858:Metabolic Networks and Pathways; D019579:Neocortex / Q000166:cytology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013574:Synaptosomes / Q000378:metabolism*
chemical_list: D027322:Amino Acid Transport System X-AG; D000596:Amino Acids; D002247:Carbon Isotopes; D005632:Fructose; D005985:Glyceraldehyde; D005631:Fructokinases; D006593:Hexokinase; C021475:ketohexokinase; D005634:Fructose-Bisphosphate Aldolase; D005947:Glucose
keywords: Alzheimer's disease; Glut5; brain metabolism; fructose; glyceraldehyde; ketohexokinase