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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

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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.

Materials and 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 β-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.

Conclusion

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.

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Acknowledgments

We acknowledge the research infrastructure provided by the Norwegian Microarray Consortium (NMC; www.microarray.no), a national FUGE technology platform (Functional Genomics in Norway; www.fuge.no). The present study has been supported by grants from the Research Council of Norway (incl. the FUGE program and “PSYKISK HELSE” program), Helse Vest RHF, Dr. Einar Martens Fund, and the Lundbeck Foundation through a research grant to JF, awarded by the Scandinavian College of Neuro-Psychopharmacology (SCNP). We highly appreciate the excellent technical assistance from Marianne S. Nævdal in the animal facility. The authors also thank Erling Dahl Borkamo for assistance with the digital microscopy.

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Authors and Affiliations

  1. Department of Clinical Medicine, Dr. Einar Martens’ Research Group for Biological Psychiatry and Bergen Mental Health, Research Center, University of Bergen, Bergen, Norway

    Johan Fernø, Audun O. Vik-Mo, Goran Jassim, Bjarte Håvik, Silje Skrede & Vidar M. Steen

  2. Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway

    Johan Fernø, Audun O. Vik-Mo, Goran Jassim, Bjarte Håvik, Silje Skrede & Vidar M. Steen

  3. The Lipid Research Group, Section of Medical Biochemistry, Institute of Medicine, University of Bergen, Bergen, Norway

    Kjetil Berge, Oddrun A. Gudbrandsen & Rolf K. Berge

  4. Department of Clinical Medicine, Section for Psychiatry, University of Bergen, Bergen, Norway

    Jo Waage & Hugo A. Jørgensen

  5. Department of Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway

    Niclas Lunder

  6. Department of Pathology, The Gade Institute, Haukeland University Hospital, Bergen, Norway

    Sverre Mørk

  7. Department of Cardiovascular Disease, Haukeland University Hospital, Bergen, Norway

    Rolf K. Berge

  8. Division of Psychiatry, Helse Bergen HF, Bergen, Norway

    Hugo A. Jørgensen

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  1. Johan Fernø
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  2. Audun O. Vik-Mo
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  3. Goran Jassim
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Correspondence to Johan Fernø.

Additional information

Audun O. Vik-Mo and Goran Jassim have contributed equally to the study.

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Fernø, J., Vik-Mo, A.O., Jassim, G. et al. 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. Psychopharmacology 203, 73–84 (2009). https://doi.org/10.1007/s00213-008-1370-x

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