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

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 Ca2+ 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 Ca2+ 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’.

► We propose an explanation to the antipsychotic drugs (APDs) metabolic disturbances.
► We used the Immortalized Human Hepatocyte cell line as an original model.
► We show that APDs trigger Endoplasmic Reticulum (ER) stress via the PERK pathway.
► These APDs also modulate the SREBP pathways provoking cellular lipid accumulation.
► Clozapine induces ER stress by modifying intracellular calcium concentrations.