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Activation of the PERK-CHOP signaling pathway during endoplasmic reticulum stress contributes to olanzapine-induced dyslipidemia

Acta Pharmacologica Sinica volume 45, pages 502–516 (2024)Cite this article

Abstract

Olanzapine (OLZ) is a widely prescribed antipsychotic drug with a relatively ideal effect in the treatment of schizophrenia (SCZ). However, its severe metabolic side effects often deteriorate clinical therapeutic compliance and mental rehabilitation. The peripheral mechanism of OLZ-induced metabolic disorders remains abstruse for its muti-target activities. Endoplasmic reticulum (ER) stress is implicated in cellular energy metabolism and the progression of psychiatric disorders. In this study, we investigated the role of ER stress in the development of OLZ-induced dyslipidemia. A cohort of 146 SCZ patients receiving OLZ monotherapy was recruited, and blood samples and clinical data were collected at baseline, and in the 4th week, 12th week, and 24th week of the treatment. This case-control study revealed that OLZ treatment significantly elevated serum levels of endoplasmic reticulum (ER) stress markers GRP78, ATF4, and CHOP in SCZ patients with dyslipidemia. In HepG2 cells, treatment with OLZ (25, 50 μM) dose-dependently enhanced hepatic de novo lipogenesis accompanied by SREBPs activation, and simultaneously triggered ER stress. Inhibition of ER stress by tauroursodeoxycholate (TUDCA) and 4-phenyl butyric acid (4-PBA) attenuated OLZ-induced lipid dysregulation in vitro and in vivo. Moreover, we demonstrated that activation of PERK-CHOP signaling during ER stress was a major contributor to OLZ-triggered abnormal lipid metabolism in the liver, suggesting that PERK could be a potential target for ameliorating the development of OLZ-mediated lipid dysfunction. Taken together, ER stress inhibitors could be a potentially effective intervention against OLZ-induced dyslipidemia in SCZ.

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Fig. 1: The serum level of endoplasmic reticulum (ER) stress biomarkers is elevated in schizophrenia patients with dyslipidemia after olanzapine (OLZ) treatment.
Fig. 2: OLZ promotes hepatic de novo lipogenesis and ER stress in vitro.
Fig. 3: Targeting ER stress prevents OLZ-induced hepatic de novo lipogenesis in vitro.
Fig. 4: Inhibiting ER stress ameliorates OLZ-induced lipid metabolism dysfunction in mice.
Fig. 5: Loss of PERK reverses OLZ-induced lipid disorder in vitro.
Fig. 6: Liver-specific PERK silencing improves OLZ-induced lipid dysregulation in mice.
Fig. 7: The graphical mechanism of OLZ causes lipid disorder.

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Acknowledgements

This study was supported by the Chongqing Basic Research and Frontier Exploration Project (cstc2022ycjh-bgzxm0119).

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Authors and Affiliations

  1. School of Pharmaceutical Sciences, Medical Research Institute, Southwest University, Chongqing, 400715, China

    Lu Liu, Xue-mei Liu & Chang-hua Hu

  2. NMPA Key Laboratory for Quality Monitoring of Narcotic Drugs and Psychotropic Substances, Chongqing, 400715, China

    Lu Liu, Xue-mei Liu & Chang-hua Hu

  3. School of Mental Health, North Sichuan Medical College, Nanchong, 637100, China

    Lu Liu, Lei Tang & Jia-ming Luo

  4. Mental Health Center, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637100, China

    Lei Tang & Jia-ming Luo

  5. Affiliated Nanchong Psychosomatic Hospital of North Sichuan Medical College, Nanchong, 637100, China

    Si-yu Chen & Chun-yan Yi

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CHH and LL conducted the literature searches and designed the experiments; JML, LT, SYC, CYY, and LL collected patient blood samples and clinical data; LL conducted the experiments and drafted the article in this study; CHH, XML, and LL analyzed and interpreted data, and revised the article; All authors approved the final version for submission.

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Correspondence to Chang-hua Hu.

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Liu, L., Tang, L., Luo, Jm. et al. Activation of the PERK-CHOP signaling pathway during endoplasmic reticulum stress contributes to olanzapine-induced dyslipidemia. Acta Pharmacol Sin 45, 502–516 (2024). https://doi.org/10.1038/s41401-023-01180-w

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