Atypical Antipsychotics Alter Cholesterol and Fatty Acid Metabolism in Vitro
Open accessAbstract
Haloperidol, a typical antipsychotic, has been shown to inhibit cholesterol biosynthesis by affecting Δ(7)-reductase, Δ(8,7)-isomerase, and Δ(14)-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 Δ(24)-reductase and Δ(8,7)-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.
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Among the top 10 novel enhancers of oligodendrocyte formation, four molecules had previously been shown to inhibit TM7SF2 or EBP in CNS-derived cells.
“Among the top 10 novel enhancers of oligodendrocyte formation, we noted four molecules had previously been shown to inhibit TM7SF2 or EBP in CNS-derived cells11,21”
From Accumulation of 8,9-unsaturated sterols drives oligodendrocyte formation and remyelination (2018) · cites this paper as [21]
Twenty-seven small molecules have been characterized as both enhancing myelination and elevating 8,9-unsaturated sterol intermediate levels.
“In all we have characterized twenty-seven small molecules as both enhancing myelination and elevating 8,9-unsaturated sterol intermediate levels11,21,23”
From Accumulation of 8,9-unsaturated sterols drives oligodendrocyte formation and remyelination (2018) · cites this paper as [21]
Neuroleptics inhibit cholesterol biosynthesis in vitro by reducing the activities of the enzymes involved in this pathway, leading to the accumulation of various sterol intermediates.
“Neuroleptics inhibit cholesterol biosynthesis in vitro by reducing the activities of the enzymes involved in this pathway, leading to the accumulation of various sterol intermediates [134,135].”
From Lipids in Psychiatric Disorders: Functional and Potential Diagnostic Role as Blood Biomarkers (2024) · cites this paper as [134]
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- Authors
- Canfrán-Duque, A., Casado, M. E., Pastor, Ó., Sánchez-Wandelmer, J., de la Peña, G., Lerma, M., Mariscal, P., Bracher, F., Lasunción, M. A., & Busto, R.
- Affiliations
- Instituto Ramón y Cajal de Investigación Sanitaria (ES)
- Instituto de Salud Carlos III (ES)
- Ludwig-Maximilians-Universität München (DE)
- Universidad de Alcalá (ES)
- Corresponding author
- Lasunción, Miguel A.
- Busto, Rebeca
- Venue
- Journal of Lipid Research
- Publisher
- Elsevier BV
- Published
- 2013-02
- Volume
- 54
- Issue
- 2
- Pages
- 310-324
- ISSN
- 0022-2275 (ISSN-L)
- PMC
- PMC3588861
- OpenAlex
- W1996298238
- Cited by
- 105
- References
- 60
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 6 · 2023: 8 · 2022: 5 · 2021: 10 · 2020: 4 · 2019: 12 · 2018: 8 · 2017: 7 · 2016: 13 · 2015: 8 · 2014: 8 · 2013: 4 · 2012: 1
- FWCI
- 6.84
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Lipid Research (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Keywords
- atypical antipsychotics, cholesterol biosynthesis, fatty acid metabolism, clozapine, risperidone, ziprasidone, haloperidol, endoplasmic reticulum cholesterol, SREBP, phospholipid synthesis, triglyceride synthesis, apolipoprotein B secretion, hypertriglyceridemia
- MeSH terms
- Acetates, Biological Transport, Cholesterol, Fatty Acids, Gene Expression Regulation, Homeostasis, Humans, Cholesterol, LDL, Antipsychotic Agents, Intracellular Space, Cell Line, Tumor, Apolipoprotein B-100
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