Atypical antipsychotics alter cholesterol and fatty acid metabolism in vitro[S]
Haloperidol, a typical antipsychotic, has been shown to inhibit cholesterol biosynthesis by affecting Δ7-reductase, Δ8,7-isomerase, and Δ14-reductase activities, which results in the accumulation of different sterol intermediates. In the present work, we investigated the effects of atypical or secon...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2013-02-01
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| Series: | Journal of Lipid Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S002222752042797X |
| _version_ | 1829513028186406912 |
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| author | Alberto Canfrán-Duque María E. Casado Óscar Pastor Jana Sánchez-Wandelmer Gema de la Peña Milagros Lerma Paloma Mariscal Franz Bracher Miguel A. Lasunción Rebeca Busto |
| author_facet | Alberto Canfrán-Duque María E. Casado Óscar Pastor Jana Sánchez-Wandelmer Gema de la Peña Milagros Lerma Paloma Mariscal Franz Bracher Miguel A. Lasunción Rebeca Busto |
| author_sort | Alberto Canfrán-Duque |
| collection | DOAJ |
| description | Haloperidol, a typical antipsychotic, has been shown to inhibit cholesterol biosynthesis by affecting Δ7-reductase, Δ8,7-isomerase, and Δ14-reductase activities, which results in the accumulation of different sterol intermediates. In the present work, we investigated the effects of atypical or second-generation antipsychotics (SGA), such as clozapine, risperidone, and ziprasidone, on intracellular lipid metabolism in different cell lines. All the SGAs tested inhibited cholesterol biosynthesis. Ziprasidone and risperidone had the same targets as haloperidol at inhibiting cholesterol biosynthesis, although with different relative activities (ziprasidone > haloperidol > risperidone). In contrast, clozapine mainly affected Δ24-reductase and Δ8,7-isomerase activities. These amphiphilic drugs also interfered with the LDL-derived cholesterol egress from the endosome/lysosome compartment, thus further reducing the cholesterol content in the endoplasmic reticulum. This triggered a homeostatic response with the stimulation of sterol regulatory element-binding protein (SREBP)-regulated gene expression. Treatment with SGAs also increased the synthesis of complex lipids (phospholipids and triacylglycerides). Once the antipsychotics were removed from the medium, a rebound in the cholesterol biosynthesis rate was detected, and the complex-lipid synthesis further increased. In this condition, apolipoprotein B secretion was also stimulated as demonstrated in HepG2 cells. These effects of SGAs on lipid homeostasis may be relevant in the metabolic side effects of antipsychotics, especially hypertriglyceridemia. |
| first_indexed | 2024-12-16T12:51:23Z |
| format | Article |
| id | doaj.art-a12cdca81f4a47f9b1e6b0c7c073b42d |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-16T12:51:23Z |
| publishDate | 2013-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-a12cdca81f4a47f9b1e6b0c7c073b42d2022-12-21T22:31:08ZengElsevierJournal of Lipid Research0022-22752013-02-01542310324Atypical antipsychotics alter cholesterol and fatty acid metabolism in vitro[S]Alberto Canfrán-Duque0María E. Casado1Óscar Pastor2Jana Sánchez-Wandelmer3Gema de la Peña4Milagros Lerma5Paloma Mariscal6Franz Bracher7Miguel A. Lasunción8Rebeca Busto9Servicio de Bioquímica-Investigación, Hospital Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, SpainServicio de Bioquímica-Investigación, Hospital Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain; y Servicio de Bioquímica-Clínica, Hospital Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, SpainCIBER de Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III (ISCIII), SpainServicio de Bioquímica-Investigación, Hospital Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, SpainServicio de Bioquímica-Investigación, Hospital Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, SpainServicio de Bioquímica-Investigación, Hospital Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, SpainServicio de Bioquímica-Investigación, Hospital Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, SpainDepartment Pharmazie, Ludwig Maximilians Universität München, Munich, Germany; andTo whom correspondence should be addressed. (M.A.L.) miguel.a.lasuncion@hrc.es; Servicio de Bioquímica-Investigación, Hospital Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain; y Servicio de Bioquímica-Clínica, Hospital Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain; Departamento de Bioquímica y Biología Molecular, Universidad de Alcalá, Madrid, Spain; To whom correspondence should be addressed. (R.B.) rebeca.busto@hrc.esTo whom correspondence should be addressed. (R.B.) rebeca.busto@hrc.es; Servicio de Bioquímica-Investigación, Hospital Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain; y Servicio de Bioquímica-Clínica, Hospital Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain; To whom correspondence should be addressed. (R.B.) rebeca.busto@hrc.esHaloperidol, a typical antipsychotic, has been shown to inhibit cholesterol biosynthesis by affecting Δ7-reductase, Δ8,7-isomerase, and Δ14-reductase activities, which results in the accumulation of different sterol intermediates. In the present work, we investigated the effects of atypical or second-generation antipsychotics (SGA), such as clozapine, risperidone, and ziprasidone, on intracellular lipid metabolism in different cell lines. All the SGAs tested inhibited cholesterol biosynthesis. Ziprasidone and risperidone had the same targets as haloperidol at inhibiting cholesterol biosynthesis, although with different relative activities (ziprasidone > haloperidol > risperidone). In contrast, clozapine mainly affected Δ24-reductase and Δ8,7-isomerase activities. These amphiphilic drugs also interfered with the LDL-derived cholesterol egress from the endosome/lysosome compartment, thus further reducing the cholesterol content in the endoplasmic reticulum. This triggered a homeostatic response with the stimulation of sterol regulatory element-binding protein (SREBP)-regulated gene expression. Treatment with SGAs also increased the synthesis of complex lipids (phospholipids and triacylglycerides). Once the antipsychotics were removed from the medium, a rebound in the cholesterol biosynthesis rate was detected, and the complex-lipid synthesis further increased. In this condition, apolipoprotein B secretion was also stimulated as demonstrated in HepG2 cells. These effects of SGAs on lipid homeostasis may be relevant in the metabolic side effects of antipsychotics, especially hypertriglyceridemia.http://www.sciencedirect.com/science/article/pii/S002222752042797Xsecond-generation antipsychotic drugscholesterol biosynthesislipid synthesisapolipoprotein B secretionintracellular lipid traffic |
| spellingShingle | Alberto Canfrán-Duque María E. Casado Óscar Pastor Jana Sánchez-Wandelmer Gema de la Peña Milagros Lerma Paloma Mariscal Franz Bracher Miguel A. Lasunción Rebeca Busto Atypical antipsychotics alter cholesterol and fatty acid metabolism in vitro[S] Journal of Lipid Research second-generation antipsychotic drugs cholesterol biosynthesis lipid synthesis apolipoprotein B secretion intracellular lipid traffic |
| title | Atypical antipsychotics alter cholesterol and fatty acid metabolism in vitro[S] |
| title_full | Atypical antipsychotics alter cholesterol and fatty acid metabolism in vitro[S] |
| title_fullStr | Atypical antipsychotics alter cholesterol and fatty acid metabolism in vitro[S] |
| title_full_unstemmed | Atypical antipsychotics alter cholesterol and fatty acid metabolism in vitro[S] |
| title_short | Atypical antipsychotics alter cholesterol and fatty acid metabolism in vitro[S] |
| title_sort | atypical antipsychotics alter cholesterol and fatty acid metabolism in vitro s |
| topic | second-generation antipsychotic drugs cholesterol biosynthesis lipid synthesis apolipoprotein B secretion intracellular lipid traffic |
| url | http://www.sciencedirect.com/science/article/pii/S002222752042797X |
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