title: 27-Hydroxycholesterol impairs neuronal glucose uptake through an IRAP/GLUT4 system dysregulation.
abstract: Hypercholesterolemia is associated with cognitively deteriorated states. Here, we show that excess 27-hydroxycholesterol (27-OH), a cholesterol metabolite passing from the circulation into the brain, reduced in vivo brain glucose uptake, GLUT4 expression, and spatial memory. Furthermore, patients exhibiting higher 27-OH levels had reduced18F-fluorodeoxyglucose uptake. This interplay between 27-OH and glucose uptake revealed the engagement of the insulin-regulated aminopeptidase (IRAP). 27-OH increased the levels and activity of IRAP, countered the IRAP antagonist angiotensin IV (AngIV)-mediated glucose uptake, and enhanced the levels of the AngIV-degrading enzyme aminopeptidase N (AP-N). These effects were mediated by liver X receptors. Our results reveal a molecular link between cholesterol, brain glucose, and the brain renin-angiotensin system, all of which are affected in some neurodegenerative diseases. Thus, reducing 27-OH levels or inhibiting AP-N maybe a useful strategy in the prevention of the altered glucose metabolism and memory decline in these disorders.
authors.affiliation: Division of Neurogeriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet, 141 86 Stockholm, Sweden.
authors.forename: Muhammad-Al-Mustafa
authors.identifier: 0000-0001-7320-1004
authors.initials: MA
authors.lastname: Ismail
authors.affiliation: Division of Neurogeriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet, 141 86 Stockholm, Sweden.
authors.forename: Laura
authors.initials: L
authors.lastname: Mateos
authors.affiliation: Division of Neurogeriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet, 141 86 Stockholm, Sweden.
authors.forename: Silvia
authors.initials: S
authors.lastname: Maioli
authors.affiliation: Division of Neurogeriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet, 141 86 Stockholm, Sweden.
authors.forename: Paula
authors.identifier: 0000-0002-1842-9476
authors.initials: P
authors.lastname: Merino-Serrais
authors.affiliation: Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska University Hospital, 141 86 Huddinge, Sweden.
authors.forename: Zeina
authors.initials: Z
authors.lastname: Ali
authors.affiliation: Division of Neurogeriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet, 141 86 Stockholm, Sweden.
authors.forename: Maria
authors.identifier: 0000-0003-0008-5641
authors.initials: M
authors.lastname: Lodeiro
authors.affiliation: Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet, 141 86 Stockholm, Sweden.
authors.forename: Eric
authors.identifier: 0000-0002-3115-2977
authors.initials: E
authors.lastname: Westman
authors.affiliation: Center for Research, Prevention, and Treatment of Atherosclerosis, Hadassah Hebrew University Medical Center, Jerusalem 91120, Israel.
authors.forename: Eran
authors.identifier: 0000-0001-8740-9068
authors.initials: E
authors.lastname: Leitersdorf
authors.affiliation: Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Balázs
authors.initials: B
authors.lastname: Gulyás
authors.affiliation: Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet, 141 86 Stockholm, Sweden.
authors.forename: Lars
authors.identifier: 0000-0002-9905-8426
authors.initials: L
authors.lastname: Olof-Wahlund
authors.affiliation: Division of Neurogeriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet, 141 86 Stockholm, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Winblad
authors.affiliation: Department of Radiology, Karolinska University Hospital, 141 86 Huddinge, Sweden.
authors.forename: Irina
authors.initials: I
authors.lastname: Savitcheva
authors.affiliation: Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska University Hospital, 141 86 Huddinge, Sweden.
authors.forename: Ingemar
authors.identifier: 0000-0001-6087-9190
authors.initials: I
authors.lastname: Björkhem
authors.affiliation: Division of Neurogeriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet, 141 86 Stockholm, Sweden Angel.Cedazo-Mínguez@ki.se.
authors.forename: Angel
authors.identifier: 0000-0003-4626-4864
authors.initials: A
authors.lastname: Cedazo-Mínguez
mesh_terms: D000804:Angiotensin II / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D053493:Cholestanetriol 26-Monooxygenase / Q000502:physiology; D002784:Cholesterol / Q000378:metabolism; D010122:Cystinyl Aminopeptidase / Q000502:physiology*; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000502:physiology*; D006801:Humans; D006888:Hydroxycholesterols / Q000494:pharmacology*; D000071518:Liver X Receptors / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism*
chemical_list: D051275:Glucose Transporter Type 4; D006888:Hydroxycholesterols; D000071518:Liver X Receptors; C495692:SLC2A4 protein, human; D000804:Angiotensin II; C012877:angiotensin II, des-Asp(1)-des-Arg(2)-Ile(5)-; C076996:27-hydroxycholesterol; D002784:Cholesterol; C506831:CYP27A1 protein, human; D053493:Cholestanetriol 26-Monooxygenase; D010122:Cystinyl Aminopeptidase; C105964:leucyl-cystinyl aminopeptidase; D005947:Glucose