Antidepressant drugs activate SREBP and up-regulate cholesterol and fatty acid biosynthesis in human glial cells.
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.
Raeder
Maria Baroy
MB
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.
Fernø
Johan
J
Glambek
Marte
M
Stansberg
Christine
C
Steen
Vidar M
VM
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
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