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 beta-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.
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 beta-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.
Authors: Heidi R Kast-Woelbern; Sharon L Dana; Rosemary M Cesario; Li Sun; Louise Y de Grandpre; Mason E Brooks; Deborah L Osburn; Anne Reifel-Miller; Kay Klausing; Mark D Leibowitz Journal: J Biol Chem Date: 2004-04-08 Impact factor: 5.157
Authors: B Spivak; S Roitman; Y Vered; R Mester; E Graff; Y Talmon; N Guy; N Gonen; A Weizman Journal: Clin Neuropharmacol Date: 1998 Jul-Aug Impact factor: 1.592
Authors: Maryam Rakhshandehroo; Linda M Sanderson; Merja Matilainen; Rinke Stienstra; Carsten Carlberg; Philip J de Groot; Michael Müller; Sander Kersten Journal: PPAR Res Date: 2007 Impact factor: 4.964
Authors: Yewon Cheon; Jee-Young Park; Hiren R Modi; Hyung-Wook Kim; Ho-Joo Lee; Lisa Chang; Jagadeesh S Rao; Stanley I Rapoport Journal: J Neurochem Date: 2011-09-20 Impact factor: 5.372
Authors: Kayla A Chase; Cherise Rosen; Hannah Gin; Olivia Bjorkquist; Benjamin Feiner; Robert Marvin; Sean Conrin; Rajiv P Sharma Journal: Psychiatry Res Date: 2014-11-13 Impact factor: 3.222
Authors: Matthew C Cave; Heather B Clair; Josiah E Hardesty; K Cameron Falkner; Wenke Feng; Barbara J Clark; Jennifer Sidey; Hongxue Shi; Bashar A Aqel; Craig J McClain; Russell A Prough Journal: Biochim Biophys Acta Date: 2016-03-04
Authors: Kieran J Davey; Siobhain M O'Mahony; Harriet Schellekens; Orla O'Sullivan; John Bienenstock; Paul D Cotter; Timothy G Dinan; John F Cryan Journal: Psychopharmacology (Berl) Date: 2012-01-11 Impact factor: 4.530
Authors: Hiren R Modi; Ameer Y Taha; Hyung-Wook Kim; Lisa Chang; Stanley I Rapoport; Yewon Cheon Journal: J Neurochem Date: 2012-12-06 Impact factor: 5.372
Authors: Alberto Canfrán-Duque; María E Casado; Oscar Pastor; Jana Sánchez-Wandelmer; Gema de la Peña; Milagros Lerma; Paloma Mariscal; Franz Bracher; Miguel A Lasunción; Rebeca Busto Journal: J Lipid Res Date: 2012-11-21 Impact factor: 5.922