Atypical Antipsychotic Drug Olanzapine Deregulates Hepatic Lipid Metabolism and Aortic Inflammation and Aggravates Atherosclerosis

Abstract

Background/Aims: Olanzapine, an atypical antipsychotic drug, has therapeutic effects for schizophrenia. However, clinical reports indicate that patients taking atypical antipsychotic drugs are at high risk of metabolic syndrome with unclear mechanisms. We investigated the effect of olanzapine on atherosclerosis and the mechanisms in apolipoprotein E-null (apoE^-/-) mice. Methods: ApoE^-/- mice were used as in vivo models. Western blot analysis was used to evaluate protein expression. Conventional assay kits were applied to assess the levels of cholesterol, triglycerides, free cholesterol, cholesteryl ester, fatty acids, glycerol, and cytokines. Results: Daily treatment with olanzapine (3 mg/kg body weight) for four weeks increased mean arterial blood pressure and the whitening of brown adipose tissue in mice. In addition, olanzapine impaired aortic cholesterol homeostasis and exacerbated hyperlipidemia and aortic inflammation, which accelerated atherosclerosis in mice. Moreover, lipid accumulation in liver, particularly total cholesterol, free cholesterol, fatty acids, and glycerol, was increased with olanzapine treatment in apoE^-/- mice by upregulating the expression of de novo lipid synthesis-related proteins and downregulating that of cholesterol clearance- or very low-density lipoprotein secretion-related proteins. Conclusion: Olanzapine may exacerbate atherosclerosis by deregulating hepatic lipid metabolism and worsening hyperlipidemia and aortic inflammation.

Activation of 5-HT2 Receptors Reduces Inflammation in Vascular Tissue and Cholesterol Levels in High-Fat Diet-Fed Apolipoprotein E Knockout Mice

“…This reduced vascular inflammation may also include a component resulting from the observed decrease in total plasma and LDL cholesterol by drug treatment. Consistent with our proposed model, a recent study found that the antipsychotic drug olanzapine, a 5-HT 2A receptor inverse agonist, increases serum levels of total cholesterol, non-HDL, HDL-c, and triglycerides, deregulates hepatic lipid metabolism, and increases aortic proinflammatory protein expression (VCAM-1, TNF-α, and IL-6) in apoE −/− mice 59 . Along a similar vein, the 5-HT 2C selective agonist lorcaserin effectively reduces appetite to induce weight loss, a result we do not see with ( R )-DOI in our study.…”

ApoE deficiency promotes hepatic pathology by aggravating Th17/Treg imbalance in murine schistosomiasis japonica

“…[56][57][58] ApoE deficiency has effects on both FAO and FAS. 59 The contribution of ApoE to the immune balance of Th17/Treg in our study needs more in-depth investigations.…”

“…Treg cells rely mainly on fatty acid oxidation, whereas Th17 cells demonstrate a reliance upon fatty acid synthesis 56‐58 . ApoE deficiency has effects on both FAO and FAS 59 . The contribution of ApoE to the immune balance of Th17/Treg in our study needs more in‐depth investigations.…”

Genetic Polymorphisms Associated With the Pharmacokinetics, Pharmacodynamics and Adverse Effects of Olanzapine, Aripiprazole and Risperidone

“…Moreover, atypical antipsychotics can also provoke dyslipemia or hyperlipidemia, however, the mechanisms by which this occurs are not clearly known ( Jeon and Kim, 2017 ). It is proposed that olanzapine alters hepatic lipid metabolism by interfering with lipogenesis, lipoprotein internalization and cholesterol clearance, favoring the accumulation of lipids and the development of hyperlipidemia ( Chen et al, 2018 ).…”