title: Acute clozapine exposure in vivo induces lipid accumulation and marked sequential changes in the expression of SREBP, PPAR, and LXR target genes in rat liver.
abstract: BACKGROUND
  Several antipsychotic drugs (APDs) have high propensity to induce weight gain and dyslipidemia in patients, with clozapine and olanzapine as the most potent drugs. These lipid-related effects have been attributed to drug-mediated blockade or antagonism of histamine H1 and serotonin 5-HT2 receptors as well as activation of hypothalamic AMP-activated protein kinase. We recently showed that APDs activate lipid biosynthesis in cultured liver cells through stimulation of the sterol regulatory element-binding protein (SREBP) transcription factors.
  
  
  OBJECTIVE
  The objective of the study was to search for clozapine-related lipogenic effects in peripheral tissues in vivo using rat liver as target organ.
  
  
  METHODS
  Adult female Sprague-Dawley rats were administered single intraperitoneal injections of clozapine (25 and 50 mg/kg). Hepatic lipid levels were measured during a 48-h time course. Real-time quantitative PCR was used to analyze expression of genes involved in lipid biosynthesis, oxidation, efflux, and lipolysis.
  
  
  RESULTS
  We identified an initial up-regulation of central lipogenic SREBP target genes, followed by a marked and sustained down-regulation. We also observed a sequential transcriptional response for fatty acid beta-oxidation and cholesterol efflux genes, normally controlled by the peroxisome proliferator activated receptor alpha and liver X receptor alpha transcription factors, and also down-regulation of genes encoding major lipases. The transcriptional responses were associated with a significant accumulation of triacylglycerol, phospholipids, and cholesterol in the liver.
  
  
  CONCLUSIONS
  These results demonstrate that acute clozapine exposure affects SREBP-regulated lipid biosynthesis as well as other lipid homeostasis pathways. We suggest that such drug-induced effects on lipid metabolism in peripheral tissues are relevant for the metabolic adverse effects associated with clozapine and possibly other APDs.
authors.affiliation: Department of Clinical Medicine, Dr. Einar Martens' Research Group for Biological Psychiatry and Bergen Mental Health, Research Center, University of Bergen, Bergen, Norway. johan.ferno@uib.no
authors.forename: Johan
authors.initials: J
authors.lastname: Fernø
authors.forename: Audun O
authors.initials: AO
authors.lastname: Vik-Mo
authors.forename: Goran
authors.initials: G
authors.lastname: Jassim
authors.forename: Bjarte
authors.initials: B
authors.lastname: Håvik
authors.forename: Kjetil
authors.initials: K
authors.lastname: Berge
authors.forename: Silje
authors.initials: S
authors.lastname: Skrede
authors.forename: Oddrun A
authors.initials: OA
authors.lastname: Gudbrandsen
authors.forename: Jo
authors.initials: J
authors.lastname: Waage
authors.forename: Niclas
authors.initials: N
authors.lastname: Lunder
authors.forename: Sverre
authors.initials: S
authors.lastname: Mørk
authors.forename: Rolf K
authors.initials: RK
authors.lastname: Berge
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Jørgensen
authors.forename: Vidar M
authors.initials: VM
authors.lastname: Steen
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000633:toxicity*; D002788:Cholesterol Esters / Q000378:metabolism; D003024:Clozapine / Q000008:administration & dosage / Q000633:toxicity*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D007274:Injections, Intraperitoneal; D008049:Lipase / Q000235:genetics; D050356:Lipid Metabolism / Q000187:drug effects* / Q000235:genetics; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D000071518:Liver X Receptors; D008297:Male; D057093:Orphan Nuclear Receptors; D047493:PPAR alpha / Q000378:metabolism*; D010743:Phospholipids / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism*; D013997:Time Factors; D014280:Triglycerides / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D002788:Cholesterol Esters; D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; C000605215:Nr1h3 protein, rat; D057093:Orphan Nuclear Receptors; D047493:PPAR alpha; D010743:Phospholipids; D018160:Receptors, Cytoplasmic and Nuclear; C497389:Srebf1 protein, rat; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides; D008049:Lipase; D003024:Clozapine