Olanzapine-induced liver injury in mice: aggravation by high-fat diet and protection with sulforaphane

• Type of Material: Article
• Authors: Robin H Isaacson, Emory University; Juliane I Beier, Pittsburgh Liver Research Center; Nicholas KH Khoo, Department of Pharmacology and Chemical Biology; Bruce A Freeman, Vascular Medicine Institute; Zachary Freyberg, University of Pittsburgh; Gavin E Arteel, Pittsburgh Liver Research Center
• Language: English
• Date: 2020-07-01
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2020 Elsevier Inc. All rights reserved.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.jnutbio.2020.108399
• Title of Journal or Parent Work: JOURNAL OF NUTRITIONAL BIOCHEMISTRY
• Volume: 81
• Grant/Funding Information: This work was supported by NIH grants R01AA021978, P50AA024337 and P30DKDK120531 (GEA), R01HL64937, R01HL132550 and P01-HL103455 (BAF), K01DK096042 (JIB) and University of Pittsburgh Medical Center Competitive Medical Research Fund Award (N.K.H.K.).; RHI was supported by a predoctoral fellowship (T32EF011564).
• Keywords: oxidative stress; olanzapine; NAFLD; HFD; liver; sulforaphane

Abstract

Olanzapine is effective to treat for schizophrenia and other mood disorders, but limited by side effects such as weight gain, dyslipidemia, and liver injury. Obesity in the US is at epidemic levels, and is a significant risk factor for drug-induced liver injury. Obesity incidence in the psychiatric population is even higher than in the US population as a whole. The purpose of this study was to test the hypothesis that obesity worsens olanzapine-induced hepatic injury, and to investigate the potential protective effects of sulforaphane. 8-week old female C57BL/6 mice were fed either a high-fat or low-fat control diet (HFD and LFD). Mice also received either olanzapine (8 mg/kg/d) or vehicle by osmotic minipump for 4 weeks. A subset of mice in the HFD + olanzapine group was administered sulforaphane, a prototypical Nrf2 inducer (90 mg/kg/d). Olanzapine alone increased body weight, without a commensurate increase in food consumption. Olanzapine also caused hepatic steatosis and injury. Combining olanzapine and HFD caused further dysregulation of glucose and lipid metabolism. Liver damage from concurrent HFD and olanzapine was worse than liver damage from high-fat diet or olanzapine alone. Sulforaphane alleviated many metabolic side effects of olanzapine and HFD. Taken together, these data show that olanzapine dysregulates glucose and lipid metabolism and exacerbates hepatic changes caused by eating a HFD. Activation of the intrinsic antioxidant defense pathway with sulforaphane can partially prevent these effects of olanzapine and may represent a useful strategy to protect against liver injury.