Does endoplasmic reticulum stress participate in APD-induced hepatic metabolic dysregulation?

Neuropharmacology. 2012 Feb;62(2):784-96. doi: 10.1016/j.neuropharm.2011.08.048. Epub 2011 Sep 10.


Metabolic side effects caused by certain antipsychotic drugs (APDs), in particular clozapine and olanzapine, are now clinically well-documented. However, the potential mechanisms implicated in the metabolic disturbances of these drugs on peripheral tissues remain obscure. Here, we investigated the effects of five frequently prescribed APDs on the Sterol Regulatory Element Binding Protein (SREBP) transcription factor pathways which control lipogenesis and cholesterogenesis, using the Immortalized Human Hepatocyte cell model (IHH). First, clozapine, haloperidol, olanzapine and risperidone activated, at different levels, SREBP-1 activity reflected by an increased expression of SREBP-1 target genes involved in fatty acid biosynthesis (SREBP-1, FAS and/or SCD1) resulting in an accumulation of intracellular lipids. Second, clozapine and haloperidol also stimulated the SREBP-2 pathway associated with an increase in HMGCoAR expression. In contrast, quetiapine did not affect either the SREBP-1 or -2 pathways, but induced a slight accumulation of intracellular lipids. Interestingly, clozapine, haloperidol and olanzapine induced Endoplasmic Reticulum (ER) stress and, more precisely, initiation of the ER stress-activated eIF2α kinase (PERK) branch of the Unfolded Protein Response (UPR). Furthermore, treatment with thapsigargin, which increases intracellular calcium release, induced both ER stress and SREBP-1 and -2 pathway activation, whereas Ca(2+) chelation by BAPTA completely reversed the lipogenic effects and ER stress induction produced by clozapine. Based on these results, we propose that certain APDs induce ER stress via changes in Ca(2+) homeostasis in hepatocytes. This phenomenon potentially underlies a part of their known undesirable hepatic metabolic side effects. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.

MeSH terms

  • Animals
  • Antipsychotic Agents / pharmacology*
  • Calcium / metabolism
  • Cell Line
  • Cell Survival / drug effects
  • Endoplasmic Reticulum Stress / drug effects*
  • Endoplasmic Reticulum Stress / physiology
  • Fatty Acid Synthases / genetics
  • Fatty Acid Synthases / metabolism
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism*
  • Humans
  • Lipogenesis / drug effects
  • Liver X Receptors
  • Male
  • Orphan Nuclear Receptors / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects*
  • Stearoyl-CoA Desaturase / genetics
  • Stearoyl-CoA Desaturase / metabolism
  • Sterol Regulatory Element Binding Protein 1 / genetics
  • Sterol Regulatory Element Binding Protein 1 / metabolism
  • Unfolded Protein Response / drug effects*
  • Unfolded Protein Response / physiology


  • Antipsychotic Agents
  • Liver X Receptors
  • Orphan Nuclear Receptors
  • SREBF1 protein, human
  • Sterol Regulatory Element Binding Protein 1
  • SCD1 protein, human
  • Stearoyl-CoA Desaturase
  • Fatty Acid Synthases
  • Calcium