Insight into mechanism of in vitro insulin secretion increase induced by antipsychotic clozapine: role of FOXA1 and mitochondrial citrate carrier

Eur Neuropsychopharmacol. 2013 Aug;23(8):978-87. doi: 10.1016/j.euroneuro.2012.08.015. Epub 2012 Sep 7.

Abstract

The use of clozapine and other antipsychotic drugs is known to be associated with a number of adverse metabolic side effects, including diabetes mellitus. These side effects could be, at least in part, the result of impaired islet cell function and abnormal insulin secretion, although the underlying mechanisms are unknown. The aim of this study is the identification of targets for clozapine related to the abnormal insulin secretion. We identify a specific activation of the transcriptional factor FOXA1, but not FOXA2 and FOXA3, by clozapine in HepG2 cells. Clozapine enhances FOXA1 DNA-binding and its transcriptional activity, increasing mitochondrial citrate carrier gene expression, which contains a FOXA1 site in its promoter. Haloperidol, a conventional antipsychotic drug, does not determine any increase of FOXA1 gene expression. We also demonstrate that clozapine upregulates FOXA1 and CIC gene expression in INS-1 cells only at basal glucose concentration. In addition, we find that abnormal insulin secretion in basal glucose conditions could be completely abolished by FOXA1 silencing in INS-1 cells treated with clozapine. The identification of FOXA1 as a novel target for clozapine may shed more light to understand molecular mechanism of abnormal insulin secretion during clozapine treatment.

Keywords: Antipsychotics; Citrate carrier; Clozapine; FOXA1; Gene expression; Insulin secretion; Silencing.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anion Transport Proteins / agonists*
  • Anion Transport Proteins / biosynthesis
  • Anion Transport Proteins / genetics
  • Anion Transport Proteins / metabolism
  • Antipsychotic Agents / adverse effects
  • Antipsychotic Agents / pharmacology*
  • Cell Line
  • Clozapine / administration & dosage
  • Clozapine / pharmacology*
  • Diabetes Mellitus / chemically induced
  • Gene Expression Regulation / drug effects
  • Gene Silencing
  • Glucose / metabolism
  • Haloperidol / adverse effects
  • Haloperidol / pharmacology
  • Hep G2 Cells
  • Hepatocyte Nuclear Factor 3-alpha / agonists*
  • Hepatocyte Nuclear Factor 3-alpha / antagonists & inhibitors
  • Hepatocyte Nuclear Factor 3-alpha / genetics
  • Hepatocyte Nuclear Factor 3-alpha / metabolism
  • Humans
  • Insulin / metabolism*
  • Insulin Secretion
  • Insulin-Secreting Cells / drug effects*
  • Insulin-Secreting Cells / metabolism
  • Mitochondrial Proteins / agonists*
  • Mitochondrial Proteins / biosynthesis
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism
  • Promoter Regions, Genetic / drug effects
  • RNA, Messenger / metabolism
  • RNA, Small Interfering
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism
  • Response Elements / drug effects
  • Up-Regulation / drug effects*

Substances

  • Anion Transport Proteins
  • Antipsychotic Agents
  • FOXA1 protein, human
  • Hepatocyte Nuclear Factor 3-alpha
  • Insulin
  • Mitochondrial Proteins
  • RNA, Messenger
  • RNA, Small Interfering
  • Recombinant Proteins
  • Slc25a1 protein, human
  • Glucose
  • Clozapine
  • Haloperidol