title: Fluoxetine induces hepatic lipid accumulation via both promotion of the SREBP1c-related lipogenesis and reduction of lipolysis in primary mouse hepatocytes.
abstract: OBJECTIVE
  In this study, we investigated the peripheral mechanisms underlying the metabolic side effects of fluoxetine (FLX) by focusing on hepatic lipid metabolism.
  
  
  METHODS
  Primary mouse hepatocytes were prepared from male mice by the two-step perfusion method. The lipid accumulation in primary mouse hepatocytes was analyzed via neutral oil staining. And the lipid metabolism enzymes were determined with RT-PCR and Western blot.
  
  
  RESULTS
  Fluoxetine significantly induced the lipid accumulation in primary mouse hepatocytes. Moreover, FLX increased the acetyl-CoA carboxylase 1 (ACC1) and fatty acid synthase (FAS) expression, which are important enzymes in lipogenesis. Oppositely, Fluoxetine significantly decreased the carboxylesterase 3 (CES3) and carboxylesterase 1 (CES1) expression, which are related to lipolysis. Further study demonstrated FLX-activated SREBP1c, which is one of the most important transcription factors conducting coordinated transcriptional regulation of lipogenesis gene such as ACC1 and FAS. And the increase of lipogenesis gene (ACC1) was abolished by SB203580 but not by pyrrolidine dithiocarbamate (PDTC), suggesting through p38-MAPK pathway.
  
  
  CONCLUSIONS
  Fluoxetine induces hepatic lipid accumulation via both promotion of the SREBP1c-related lipogenesis and reduction of lipolysis in primary mouse hepatocytes.
authors.affiliation: Department of Pharmacology, Nanjing Medical University, Nanjing, China.
authors.forename: Xue-Min
authors.initials: XM
authors.lastname: Feng
authors.forename: Jing
authors.initials: J
authors.lastname: Xiong
authors.forename: Hao
authors.initials: H
authors.lastname: Qin
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Rui-Ni
authors.initials: RN
authors.lastname: Chen
authors.forename: Wei
authors.initials: W
authors.lastname: Shang
authors.forename: Rui
authors.initials: R
authors.lastname: Ning
authors.forename: Gang
authors.initials: G
authors.lastname: Hu
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
mesh_terms: D000123:Acetyltransferases / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005473:Fluoxetine / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects*; D050155:Lipogenesis / Q000187:drug effects*; D008066:Lipolysis / Q000187:drug effects*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D012333:RNA, Messenger / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D019014:fas Receptor / Q000378:metabolism
chemical_list: D000123:Acetyltransferases; D002265:Carboxylic Ester Hydrolases; D004791:Enzyme Inhibitors; D005473:Fluoxetine; D012333:RNA, Messenger; D017367:Selective Serotonin Reuptake Inhibitors; D051780:Sterol Regulatory Element Binding Protein 1; D019014:fas Receptor; C491899:Fas protein, mouse; C497388:Srebf1 protein, mouse; C055210:aminoglycoside N1-acetyltransferase