Chronic unpredictive mild stress leads to altered hepatic metabolic profile and gene expression.

Hong-Mei Jia,Hong-Wu Zhang,Zhong-Mei Zou,Meng Yu,Gang Ding,Yong Yang,Chao Zhou,Qi Li,Hai Shang

doi:10.1038/srep23441

Abstract

Depression is a complex disease characterized by a series of pathological changes. Research on depression is mainly focused on the changes in brain, but not on liver. Therefore, we initially explored the metabolic profiles of hepatic extracts from rats treated with chronic unpredictive mild stress (CUMS) by UPLC-Q-TOF/MS. Using multivariate statistical analysis, a total of 26 altered metabolites distinguishing CUMS-induced depression from normal control were identified. Using two-stage receiver operating characteristic (ROC) analysis, 18 metabolites were recognized as potential biomarkers related to CUMS-induced depression via 12 metabolic pathways. Subsequently, we detected the mRNA expressions levels of apoptosis-associated genes such as Bax and Bcl-2 and four key enzymes including Pla2g15, Pnpla6, Baat and Gad1 involved in phospholipid and primary bile acid biosynthesis in liver tissues of CUMS rats by real-time qRT-PCR assay. The expression levels of Bax, Bcl-2, Pla2g15, Pnpla6 and Gad1 mRNA were 1.43,1.68, 1.74, 1.67 and 1.42-fold higher, and those of Baat, Bax/Bcl-2 ratio mRNA were 0.83, 0.85-fold lower in CUMS rats compared with normal control. Results of liver-targeted metabonomics and mRNA expression demonstrated that CUMS-induced depression leads to variations in hepatic metabolic profile and gene expression, and ultimately results in liver injury.

Highlights

Depression is a complex disease characterized by a series of pathological changes
Hepatic metabolic profile and gene expression were performed by HILIC-UPLC and RP-UPLC coupled with mass spectrometry and real-time quantitative real-time polymerase chain reaction (qRT-PCR) to investigate the liver response to Chronic unpredictable mild stress (CUMS)-induced depression
A panel of 18 altered metabolites was identified as potential biomarkers related to depression via a two-stage receiver operating characteristic (ROC) analysis of metabonomics data

Summary

Introduction

Depression is a complex disease characterized by a series of pathological changes. Research on depression is mainly focused on the changes in brain, but not on liver. Depression is a widespread psychiatric illness ranked by the World Health Organization (WHO) as one of the most burdensome diseases of society[1,2] It is characterized by a series of pathological stages associated with stressful events, leading to low morale, weight loss and anhedonia[3,4]. Metabonomics is the study of the metabolic response of living systems to genetic or environmental stimuli[13] It provides a deeper understanding of global perturbations in metabolites and biochemical pathways in diseases, especially complex diseases[14]. Targeted liver tissue metabonomics can provide a unique perspective of the dynamic and complex metabolic changes, since liver plays a key role in a series of physiological and biochemical reactions, including synthesis, decomposition, excretion, transformation and other metabolic processes. Metabolite fluctuations provide a real functional endpoint of cellular www.nature.com/scientificreports/

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Conclusion