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Antipsychotic drug action on SREBPs-related lipogenesis and cholesterogenesis in primary rat hepatocytes

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Abstract

The use of some of antipsychotic drugs (APDs) in humans has been hampered by the induction of metabolic disorders such as weight gain, dyslipidemia, and diabetes. In primary rat hepatocytes, we investigated the actions of several APDs on lipid and cholesterol metabolism using [14C]acetate incorporation, quantitative reverse transcription-polymerase chain reaction, and western blotting. Clozapine and olanzapine, known to have significant metabolic side effects in man, strongly increased de novo lipid and cholesterol synthesis in rat hepatocytes. Haloperidol, which has less impact in metabolic disorders, enhanced lipogenesis without altering cholesterol production. By contrast, quetiapine, which exhibits few metabolic side effects in man, did not affect lipid and cholesterol synthesis. Interestingly, aripiprazole, which has not yet been reported to induce metabolic disorders in humans, strongly decreases cholesterol synthesis. Furthermore, these inductions of lipid and cholesterol synthesis observed with clozapine and olanzapine were also associated with up-regulation of the transcription factors sterol regulatory element-binding protein (SREBP)-1 and/or SREBP-2 and their associated target genes. Part of the APD-induced metabolic disorders in humans may be due to direct effects on liver metabolism. Our model may also be of interest to assess the action of future drugs on metabolic parameters.

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Abbreviations

ABCA1:

adenosine triphosphate-binding cassette transporter A1

ACAT:

acyl-coenzyme A:cholesterol acyltransferase

ACC1:

acetyl-CoA carboxylase 1

APD:

antipsychotic drug

CE:

cholesteryl esters

CPT1A:

carnitine palmitoyltransferase 1A

EPS:

extrapyramidal symptoms

ER:

endoplasmic reticulum

FAS:

fatty acid synthase

FC:

free cholesterol

FFA:

free fatty acid

HMGCoAR:

3-hydroxy-3-methylglutaryl-CoA reductase

PPARα:

peroxisome proliferator-activated receptor-α

LDLR:

low-density lipoprotein receptor

RPLPO:

ribosomal protein P0

SOAT1:

sterol O-acyltransferase 1

SCD1:

stearoyl-CoA desaturase 1

SGA:

second generation of antipsychotic drugs

SREBP-1:

sterol regulatory element-binding protein-1

SREBP-2:

sterol regulatory element-binding protein-2

TG:

triacylglycerides

VLDL:

very-low-density lipoprotein

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Acknowledgments

This study has been financially supported by the Pierre Fabre Company. We would thank S. Bessou-Touya, D. Junquero, and C. Lou for the helpful discussions; L.Puech, S. Breand, and the zootechnical service for their technical expertise; and Luc De Vries for critically reading the manuscript.

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Authors and Affiliations

  1. Department of Cellular and Molecular Biology, Pierre Fabre Research Center, 17 avenue Jean Moulin, 81106, Castres Cedex, France

    Emilie Lauressergues & Didier Cussac

  2. Université Lille Nord de France, Inserm U545, UDSL, Institut Pasteur de Lille, 59000, Lille, France

    Bart Staels

  3. Department of Cardiovascular Diseases, Pierre Fabre Research Center, 17 avenue Jean Moulin, 81106, Castres Cedex, France

    Karine Valeille

  4. Genfit SA, Parc Eurasanté, 59120, Loos, France

    Zouher Majd & Dean W. Hum

  5. Department of Medical Pharmacology, EA 1046, Faculty of Medicine, Institute of Predictive Medicine and of Therapeutics Research, University of Lille 2, 59045, Lille, France

    Patrick Duriez

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  1. Emilie Lauressergues
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Correspondence to Emilie Lauressergues.

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Lauressergues, E., Staels, B., Valeille, K. et al. Antipsychotic drug action on SREBPs-related lipogenesis and cholesterogenesis in primary rat hepatocytes. Naunyn-Schmied Arch Pharmacol 381, 427–439 (2010). https://doi.org/10.1007/s00210-010-0499-4

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