title: Effect of cholesterol reduction on receptor signaling in neurons.
abstract: Diabetes mellitus is associated with a variety of complications, including alterations in the central nervous system (CNS). We have recently shown that diabetes results in a reduction of cholesterol synthesis in the brain due to decreased insulin stimulation of SREBP2-mediated cholesterol synthesis in neuronal and glial cells. In the present study, we explored the effects of the decrease in cholesterol on neuronal cell function using GT1-7 hypothalamic cells subjected to cholesterol depletion in vitro using three independent methods: 1) exposure to methyl-β-cyclodextrin, 2) treatment with the HMG-CoA reductase inhibitor simvastatin, and 3) shRNA-mediated knockdown of SREBP2. All three methods produced 20-31% reductions in cellular cholesterol content, similar to the decrease in cholesterol synthesis observed in diabetes. All cholesterol-depleted neuron-derived cells, independent of the method of reduction, exhibited decreased phosphorylation/activation of IRS-1 and AKT following stimulation by insulin, insulin-like growth factor-1, or the neurotrophins (NGF and BDNF). ERK phosphorylation/activation was also decreased after methyl-β-cyclodextrin and statin treatment but increased in cells following SREBP2 knockdown. In addition, apoptosis in the presence of amyloid-β was increased. Reduction in cellular cholesterol also resulted in increased basal autophagy and impairment of induction of autophagy by glucose deprivation. Together, these data indicate that a reduction in neuron-derived cholesterol content, similar to that observed in diabetic brain, creates a state of insulin and growth factor resistance that could contribute to CNS-related complications of diabetes, including increased risk of neurodegenerative diseases, such as Alzheimer disease.
authors.affiliation: From the Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215.
authors.forename: Kenji
authors.initials: K
authors.lastname: Fukui
authors.affiliation: From the Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215.
authors.forename: Heather A
authors.initials: HA
authors.lastname: Ferris
authors.affiliation: From the Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215 c.ronald.kahn@joslin.harvard.edu.
authors.forename: C Ronald
authors.initials: CR
authors.lastname: Kahn
mesh_terms: D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism*; D007031:Hypothalamus / Q000166:cytology / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D051379:Mice; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D051782:Sterol Regulatory Element Binding Protein 2; D047392:beta-Cyclodextrins / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D019208:Brain-Derived Neurotrophic Factor; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; C497391:Srebf2 protein, mouse; D051782:Sterol Regulatory Element Binding Protein 2; D047392:beta-Cyclodextrins; C519530:insulin-like growth factor-1, mouse; C108732:methyl-beta-cyclodextrin; D007334:Insulin-Like Growth Factor I; D020932:Nerve Growth Factor; D002784:Cholesterol; D051057:Proto-Oncogene Proteins c-akt
keywords: apoptosis; brain; cholesterol; diabetes; insulin; insulin-like growth factor (IGF); membrane lipid; neurotrophin