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Activation of the PERK-CHOP signaling pathway during endoplasmic reticulum stress contributes to olanzapine-induced dyslipidemia.
Liu, Lu; Tang, Lei; Luo, Jia-Ming; Chen, Si-Yu; Yi, Chun-Yan; Liu, Xue-Mei; Hu, Chang-Hua.
Affiliation
  • Liu L; School of Pharmaceutical Sciences, Medical Research Institute, Southwest University, Chongqing, 400715, China.
  • Tang L; NMPA Key Laboratory for Quality Monitoring of Narcotic Drugs and Psychotropic Substances, Chongqing, 400715, China.
  • Luo JM; School of Mental Health, North Sichuan Medical College, Nanchong, 637100, China.
  • Chen SY; School of Mental Health, North Sichuan Medical College, Nanchong, 637100, China.
  • Yi CY; Mental Health Center, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637100, China.
  • Liu XM; School of Mental Health, North Sichuan Medical College, Nanchong, 637100, China.
  • Hu CH; Mental Health Center, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637100, China.
Acta Pharmacol Sin ; 45(3): 502-516, 2024 Mar.
Article in En | MEDLINE | ID: mdl-37880338
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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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Signal Transduction / Dyslipidemias Limits: Humans Language: En Journal: Acta Pharmacol Sin Journal subject: FARMACOLOGIA Year: 2024 Document type: Article Affiliation country: China Country of publication: United States

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Signal Transduction / Dyslipidemias Limits: Humans Language: En Journal: Acta Pharmacol Sin Journal subject: FARMACOLOGIA Year: 2024 Document type: Article Affiliation country: China Country of publication: United States