Antipsychotic-induced increase in lipid biosynthesis: activation through inhibition?

Skrede, Sverre; Steen, Vidar M.; Fernø, Johan

doi:10.1194/jlr.e034736

Cited by 17 publications

(14 citation statements)

References 24 publications

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“…HDL and LDL cholesterol parameters, leptin and leptin/adiponectin ratio were significantly reduced, while TAG, AI, AIP, and adiponectin were massively increased in the MAM‐OLA responder group compared to the CTR‐OLA group. These effects were in line with previous acute studies in healthy animals, 27,32,42 supporting the current understanding of weight‐independent dysregulation of lipid metabolism 5,63 . Indeed, preclinical evidence for direct effects of antipsychotics, with consistent findings of increased TAG, possibly reflect a compensatory response to inhibited cholesterol biosynthesis 5,30,36,63 .…”

Section: Discussionsupporting

confidence: 86%

Olanzapine, but not haloperidol, exerts pronounced acute metabolic effects in the methylazoxymethanol rat model

Horska,

Skrede,

Kucera

et al. 2024

CNS Neurosci Ther

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AimWidely used second‐generation antipsychotics are associated with adverse metabolic effects, contributing to increased cardiovascular mortality. To develop strategies to prevent or treat adverse metabolic effects, preclinical models have a clear role in uncovering underlying molecular mechanisms. However, with few exceptions, preclinical studies have been performed in healthy animals, neglecting the contribution of dysmetabolic features inherent to psychotic disorders.MethodsIn this study, methylazoxymethanol acetate (MAM) was prenatally administered to pregnant Sprague–Dawley rats at gestational day 17 to induce a well‐validated neurodevelopmental model of schizophrenia mimicking its assumed pathogenesis with persistent phenotype. Against this background, the dysmetabolic effects of acute treatment with olanzapine and haloperidol were examined in female rats.ResultsPrenatally MAM‐exposed animals exhibited several metabolic features, including lipid disturbances. Half of the MAM rats exposed to olanzapine had pronounced serum lipid profile alteration compared to non‐MAM controls, interpreted as a reflection of a delicate MAM‐induced metabolic balance disrupted by olanzapine. In accordance with the drugs' clinical metabolic profiles, olanzapine‐associated dysmetabolic effects were more pronounced than haloperidol‐associated dysmetabolic effects in non‐MAM rats and rats exposed to MAM.ConclusionOur results demonstrate metabolic vulnerability in female prenatally MAM‐exposed rats, indicating that findings from healthy animals likely provide an underestimated impression of metabolic dysfunction associated with antipsychotics. In the context of metabolic disturbances, neurodevelopmental models possess a relevant background, and the search for adequate animal models should receive more attention within the field of experimental psychopharmacology.

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Section: Discussionsupporting

confidence: 86%

Olanzapine, but not haloperidol, exerts pronounced acute metabolic effects in the methylazoxymethanol rat model

Horska,

Skrede,

Kucera

et al. 2024

CNS Neurosci Ther

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“…Furthermore, olanzapine depot injection significantly reduced cholesterol and triglyceride levels in the liver, both in ad libitum-fed and in pair-fed rats, which is puzzling considering the hepatic transcriptional activation of key genes in lipid biosynthesis. However, in line with earlier findings, recent in vitro studies demonstrated that antipsychotics may in fact inhibit cholesterol biosynthesis at the enzymatic level, and the observed concomitant activation of SREBP-controlled gene expression was explained as a feedback response (Canfran-Duque et al, 2013;Kristiana et al, 2010;Sanchez-Wandelmer et al, 2009;Skrede et al, 2013;Summerly and Yardley, 1965). Our current finding of reduced hepatic cholesterol levels and increased plasma triglyceride levels are in accordance with this hypothesis, but the reduced hepatic triglyceride levels remain unexplained, and further studies are required to elucidate this phenomenon.…”

Section: Discussionmentioning

confidence: 55%

Olanzapine depot formulation in rat: a step forward in modelling antipsychotic-induced metabolic adverse effects

Skrede

Martins

Berge

et al. 2013

Int. J. Neuropsychopharm.

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Rats are used as animal models in the study of antipsychotic-induced metabolic adverse effects, with oral drug administration yielding hyperphagia, weight gain and, in some cases, lipogenic effects. However, the rapid half-life of these drugs in rats, in combination with development of drug tolerance after a few weeks of treatment, has limited the validity of the model. In order to prevent fluctuating drug serum concentrations seen with daily repeated administrations, we injected female rats with a single intramuscular dose of long-acting olanzapine formulation. The olanzapine depot injection yielded plasma olanzapine concentrations in the range of those achieved in patients, and induced changes in metabolic parameters similar to those previously observed with oral administration, including increased food intake, weight gain and elevated plasma triglycerides. Moreover, the sensitivity to olanzapine was maintained beyond the 2-3 wk of weight gain observed with oral administration. In a separate olanzapine depot experiment, we aimed to clarify the role of hypothalamic AMP-activated protein kinase (AMPK) in olanzapine-induced weight gain, which has been subject to debate. Adenovirus-mediated inhibition of AMPK was performed in the arcuate (ARC) or the ventromedial hypothalamic (VMH) nuclei in female rats, with subsequent injection of olanzapine depot solution. Inhibition of AMPK in the ARC, but not in the VMH, attenuated the weight-inducing effect of olanzapine, suggesting an important role for ARC-specific AMPK activation in mediating the orexigenic potential of olanzapine. Taken together, olanzapine depot formulation provides an improved mode of drug administration, preventing fluctuating plasma concentrations, reducing handling stress and opening up possibilities to perform complex mechanistic studies.

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“…Antipsychotics have been shown to affect lipid homeostasis [ 11 , 12 , 13 , 14 , 15 ]. FGAs and SGAs reduce cholesterol biosynthesis by inhibiting the activities of several enzymes in the final steps of the pathway, which leads to the accumulation of sterol intermediates.…”

Section: Introductionmentioning

confidence: 99%

First-Generation Antipsychotic Haloperidol Alters the Functionality of the Late Endosomal/Lysosomal Compartment in Vitro

Canfrán‐Duque

Barrio

Lerma

et al. 2016

IJMS

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First- and second-generation antipsychotics (FGAs and SGAs, respectively), have the ability to inhibit cholesterol biosynthesis and also to interrupt the intracellular cholesterol trafficking, interfering with low-density lipoprotein (LDL)-derived cholesterol egress from late endosomes/lysosomes. In the present work, we examined the effects of FGA haloperidol on the functionality of late endosomes/lysosomes in vitro. In HepG2 hepatocarcinoma cells incubated in the presence of 1,1′-dioctadecyl-3,3,3,3′-tetramethylindocarbocyanineperchlorate (DiI)-LDL, treatment with haloperidol caused the enlargement of organelles positive for late endosome markers lysosome-associated membrane protein 2 (LAMP-2) and LBPA (lysobisphosphatidic acid), which also showed increased content of both free-cholesterol and DiI derived from LDL. This indicates the accumulation of LDL-lipids in the late endosomal/lysosomal compartment caused by haloperidol. In contrast, LDL traffic through early endosomes and the Golgi apparatus appeared to be unaffected by the antipsychotic as the distribution of both early endosome antigen 1 (EEA1) and coatomer subunit β (β-COP) were not perturbed. Notably, treatment with haloperidol significantly increased the lysosomal pH and decreased the activities of lysosomal protease and β-d-galactosidase in a dose-dependent manner. We conclude that the alkalinization of the lysosomes’ internal milieu induced by haloperidol affects lysosomal functionality.

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Antipsychotic-induced increase in lipid biosynthesis: activation through inhibition?

Cited by 17 publications

References 24 publications

Olanzapine, but not haloperidol, exerts pronounced acute metabolic effects in the methylazoxymethanol rat model

Olanzapine, but not haloperidol, exerts pronounced acute metabolic effects in the methylazoxymethanol rat model

Olanzapine depot formulation in rat: a step forward in modelling antipsychotic-induced metabolic adverse effects

First-Generation Antipsychotic Haloperidol Alters the Functionality of the Late Endosomal/Lysosomal Compartment in Vitro

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