title: Antidepressant drugs activate SREBP and up-regulate cholesterol and fatty acid biosynthesis in human glial cells.
abstract: Dysfunction of glial lipid metabolism and abnormal myelination has recently been reported in both schizophrenia and bipolar disorder. Cholesterol is a major component of myelin, and glia-produced cholesterol serves as a glial growth factor in synaptogenesis. We have recently demonstrated that antipsychotic drugs activate the sterol regulatory element-binding protein (SREBP) transcription factors in human and rat glial cells, with subsequent up-regulation of numerous downstream genes involved in cholesterol and fatty acid biosynthesis. Since this stimulation of cellular lipogenesis could represent a new mechanism of action of psychotropic drugs, we investigated whether antidepressants and mood-stabilizers were able to induce a similar activation of SREBP-controlled lipid biosynthesis. Cultured human glioma cells (GaMg) were exposed to the antidepressant drugs imipramine, amitriptyline, clomipramine, citalopram, fluoxetine, mirtazapine and bupropion and the mood-stabilizers/antiepileptics lithium, valproate and carbamazepine. All antidepressant drugs activated the SREBP system with subsequent up-regulation of the downstream lipogenesis-related genes, although to a markedly different extent. The mood-stabilizers did not affect the SREBPs or the downstream genes. These results link antidepressant drugs, but not mood-stabilizers, to SREBP-mediated activation of cellular lipogenesis, and demonstrate a functional similarity between antipsychotic and antidepressant molecular drug action.
authors.affiliation: Dr. Einar Martens' Research Group for Biological Psychiatry and Bergen Mental Health, Research Center, Section for Medical Genetics and Molecular Medicine, University of Bergen, Norway.
authors.forename: Maria Baroy
authors.initials: MB
authors.lastname: Raeder
authors.forename: Johan
authors.initials: J
authors.lastname: Fernø
authors.forename: Marte
authors.initials: M
authors.lastname: Glambek
authors.forename: Christine
authors.initials: C
authors.lastname: Stansberg
authors.forename: Vidar M
authors.initials: VM
authors.lastname: Steen
mesh_terms: D000928:Antidepressive Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002784:Cholesterol / Q000096:biosynthesis*; D005227:Fatty Acids / Q000096:biosynthesis*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000096:biosynthesis; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013230:Stearoyl-CoA Desaturase / Q000096:biosynthesis; D051779:Sterol Regulatory Element Binding Proteins / Q000378:metabolism*; D013778:Tetrazolium Salts; D013844:Thiazoles; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000928:Antidepressive Agents; D005227:Fatty Acids; D051779:Sterol Regulatory Element Binding Proteins; D013778:Tetrazolium Salts; D013844:Thiazoles; D002784:Cholesterol; D013230:Stearoyl-CoA Desaturase; D006904:Hydroxymethylglutaryl-CoA Synthase; C022616:thiazolyl blue