Association between clozapine-induced hypertriglyceridemia and defenestration of liver sinusoidal endothelial cells.
9 affiliations
- 1Vascular Biology Research Group, Department of Medical Biology, UiT The Arctic University of Norway, Tromsø, Norway.
- 2Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway.
- 3Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway.
- 4Translational Vascular Research Group, Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, Norway.
- 5The Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway.
- 6ANZAC Research Institute, Concord Hospital, Sydney Local Health District and Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.
- 7Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia.
- 8Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway. [email protected].
- 9Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway. [email protected].
Abstract
Clozapine is the most effective antipsychotic drug, while also causing the most severe metabolic side effects. The underlying mechanisms of these side effects appear multifactorial and are not entirely understood. We hypothesized that liver sinusoidal endothelial cells (LSEC) dysfunction is linked to the metabolic side effects of clozapine, based on known association between reduced LSEC porosity, hypertriglyceridemia and insulin resistance. Accordingly, we conducted a translational study by assessing the porosity of murine LSECs following clozapine exposure in vitro and correlating serum clozapine concentrations with metabolic parameters in routine human blood samples. The patient data showed a correlation for clozapine serum concentrations with both triglycerides (Spearman's ρ = 0.47, P = 0.00024) and glucose levels (ρ = 0.24, P = 0.034), but no correlation with LDL cholesterol (ρ = -0.04, P = 0.82) or HDL cholesterol (ρ = -0.22, P = 0.088). The in vitro experiments showed a concentration-dependent reduction in murine LSEC porosity (P for trend = 0.00036). Together, these findings support a link between clozapine exposure and reduced LSEC porosity. This represents a promising point of intervention that potentially could expand safe access to clozapine as a highly effective antipsychotic treatment for a broader population, also in individuals at high risk for metabolic and cardiovascular side effects.
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BibTeX
@article{voloshyna2026association,
title = {{Association between clozapine-induced hypertriglyceridemia and defenestration of liver sinusoidal endothelial cells.}},
author = {Tetyana Voloshyna and Øyvind V Svendsen and Karolina Szafranska and Jakub Pospíšil and Eike C Struck and Elisabet Størset and Robert L Smith and Espen Molden and David G Le Couteur and Victoria C Cogger and Peter A G McCourt and Erik S Dietrichs},
journal = {Translational psychiatry},
year = {2026},
month = aug,
doi = {10.1038/s41398-026-04328-4},
url = {https://europepmc.org/article/MED/42901887},
note = {CC BY},
}
RIS
TY - JOUR
TI - Association between clozapine-induced hypertriglyceridemia and defenestration of liver sinusoidal endothelial cells.
AU - Tetyana Voloshyna
AU - Øyvind V Svendsen
AU - Karolina Szafranska
AU - Jakub Pospíšil
AU - Eike C Struck
AU - Elisabet Størset
AU - Robert L Smith
AU - Espen Molden
AU - David G Le Couteur
AU - Victoria C Cogger
AU - Peter A G McCourt
AU - Erik S Dietrichs
PY - 2026
DA - 2026/08/01
JO - Translational psychiatry
DO - 10.1038/s41398-026-04328-4
UR - https://europepmc.org/article/MED/42901887
AB - Clozapine is the most effective antipsychotic drug, while also causing the most severe metabolic side effects. The underlying mechanisms of these side effects appear multifactorial and are not entirely understood. We hypothesized that liver sinusoidal endothelial cells (LSEC) dysfunction is linked to the metabolic side effects of clozapine, based on known association between reduced LSEC porosity, hypertriglyceridemia and insulin resistance. Accordingly, we conducted a translational study by assessing the porosity of murine LSECs following clozapine exposure in vitro and correlating serum clozapine concentrations with metabolic parameters in routine human blood samples. The patient data showed a correlation for clozapine serum concentrations with both triglycerides (Spearman's ρ = 0.47, P = 0.00024) and glucose levels (ρ = 0.24, P = 0.034), but no correlation with LDL cholesterol (ρ = -0.04, P = 0.82) or HDL cholesterol (ρ = -0.22, P = 0.088). The in vitro experiments showed a concentration-dependent reduction in murine LSEC porosity (P for trend = 0.00036). Together, these findings support a link between clozapine exposure and reduced LSEC porosity. This represents a promising point of intervention that potentially could expand safe access to clozapine as a highly effective antipsychotic treatment for a broader population, also in individuals at high risk for metabolic and cardiovascular side effects.
SN - 2158-3188
ER -