Alterations in sorting and secretion of hepatic apoA5 induce hypertriglyceridemia due to short-term use of olanzapine

Abstract

Long-term use of olanzapine, an antipsychotic drug, induces hypertriglyceridemia, resulting in a higher risk of cardiovascular disease. However, the effects and underlying mechanisms of short-term use of olanzapine on circulating triglyceride levels remain poorly understood. Here, the role of apolipoprotein A5 (apoA5), a regulator of triglyceride metabolism, was investigated in olanzapine-induced hypertriglyceridemia. Our multi-center clinical study recruited 36 schizophrenia patients who received short-term (8 weeks) of olanzapine. Besides, female C57BL/6J mice were treated with olanzapine (3 mg/kg/day versus 6 mg/kg/day) for 6 weeks. We demonstrated that short-term use of olanzapine increased plasma triglyceride and decreased plasma apoA5 levels in the patients and mice, with a negative correlation between the two factors. However, no obesity was observed in the patients and mice. Interestingly, olanzapine increased hepatic apoA5 protein in the mice, without significant changes in hepatic Apoa5 mRNA. Consistently, in vitro studies indicated that olanzapine increased medium triglyceride levels and decreased medium apoA5 levels in a dose-dependent manner in human HepG2 cells and primary mouse hepatocytes. Whereas the olanzapine treatment increased hepatic apoA5 protein in vitro, without effects on hepatic APOA5 mRNA. Of note, olanzapine increased the co-localization between apoA5 protein and accumulated lipid droplets in hepatocytes, as opposed to at the hepatocellular plasma membrane, in mouse liver as demonstrated by fluorescence staining. Therefore, our study indicated that short-term use of olanzapine induced hypertriglyceridemia due to defects of sorting and secretion of hepatic apoA5.

PCSK9 dysregulates cholesterol homeostasis and triglyceride metabolism in olanzapine‐induced hepatic steatosis via both receptor‐dependent and receptor‐independent pathways

“…Human hepatoma (HepG2) and alpha mouse liver 12 (AML12) cell lines were cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% FBS and 1% penicillin–streptomycin and were incubated with various final concentrations of olanzapine (0, 25, 50, and 100 μmol/L) for 24 h at 37°C in a humidified 5% CO 2 atmosphere. Olanzapine (LY170053, MCE, Wilkinson Way Princeton, NJ, USA) was prepared as described previously 23 . Recombinant human PCSK9 protein (rhPCSK9) was purchased from Sino Biological (29698‐H08H), and the DNA sequence encoding human PCSK9 (NP_777596.2; Met1‐Gln692) was expressed with a polyhistidine tag at the C‐terminus, at a final concentration of 500 ng/mL.…”

“…Olanzapine (LY170053, MCE, Wilkinson Way Princeton, NJ, USA) was prepared as described previously. 23 Recombinant human PCSK9 protein (rhPCSK9) was purchased from Sino Biological (29698-H08H), and the DNA sequence encoding human PCSK9 (NP_777596.2; Met1-Gln692) was expressed with a polyhistidine tag at the C-terminus, at a final concentration of 500 ng/mL. The cell line tested negative for mycoplasma contamination.…”

Characterizing defective lipid metabolism in the lateral septum of mice treated with olanzapine: implications for its side effects

“…The possibility that these atypical antipsychotic drugs may influence the molecular determinants of synaptic plasticity and brain activity while exerting their therapeutic effects also affects the central response to the side effects of these drugs ( Ibi et al, 2017 ; de Bartolomeis et al, 2022 ). Current understanding of the adverse effects induced by olanzapine indicates a complex interplay among brain activity, particularly involving the hypothalamic area and its interaction with other brain regions, though these mechanisms necessitate further clarification ( Martins et al, 2010 ; Stanley et al, 2010 ; Chen et al, 2022 ; Huang et al, 2022 ; Fang et al, 2023 ; Meng et al, 2023 ). It is highly worthwhile to explore the changes in central network functional connectivity corresponding to the induction of peripheral obesity and metabolic side effects by olanzapine.…”

Mechanism Underlying Naringenin Hypocholesterolemic Effects: Involvement of Estrogen Receptor α Subtype

“…For this purpose, HepG2 cells, which express only ERα subtype [ 24 , 25 ], have been chosen as a well-established experimental model to study lipid metabolism. Notably, this cells line retains several human liver functions, including lipid synthesis and secretion of albumin, apoB, and lipoproteins in response to various nutritional or physiological stimulations [ 26 , 27 ].…”