Untargeted Metabolomic Profiling of Liver in a Chronic Intermittent Hypoxia Mouse Model.

Xue-Jun Lin,Jie-Feng Huang,Li-Da Chen,Zhong-Ping Zhang,Zhi-Wei Huang,Yu-Zhen Huang

doi:10.3389/fphys.2021.701035

Abstract

Obstructive sleep apnea (OSA) has been demonstrated to be associated with liver injury. Nevertheless, the mechanisms linking the two disorders remain largely unexplored to date. Based on UHPLC/Q-TOF MS platform, the present study aimed to study the hepatic metabolomic profiling in a chronic intermittent hypoxia (CIH) mouse model to identify altered metabolites and related metabolic pathways. C57BL/6 Mice (n = 12 each group) were exposed to intermittent hypoxia or control conditions (room air) for 12 weeks. At the end of the exposure, liver enzymes and histological changes were assessed. Untargeted metabolomics approach by UHPLC/Q-TOF MS and orthogonal partial least squares-discriminant analysis (OPLS-DA) were applied to screen altered metabolites in mice liver. Bioinformatics analyses were applied to identify the related metabolic pathways. CIH treatment caused a remarkable liver injury in mice. A total of 27 differential metabolites in negative ion mode and 44 in positive ion mode were identified between the two groups. These metabolites were correlated to multiple biological and metabolic processes, including various amino acid metabolism, membrane transport, lipid metabolism, carbohydrate metabolism, nucleotide metabolism, ferroptosis, etc. three differential metabolites including glutathione, glutathione disulfide, arachidonic acid (peroxide free) were identified in the ferroptosis pathway. CIH was associated with a significant metabolic profiling change in mice liver. The metabolites in amino acid metabolism, membrane transport, lipid metabolism, carbohydrate metabolism, nucleotide metabolism, and ferroptosis played an important role in CIH-induced liver injury. These findings contribute to a better understanding of the mechanisms linking OSA and liver injury and help identify potential therapeutic targets.

Highlights

MATERIALS AND METHODSObstructive sleep apnea (OSA) is a breathing disorder characterized by intermittent nocturnal oxyhemoglobin desaturations and sleep disruption
The results suggested that OSA acted as an important risk factor for liver injury, especially non-alcoholic fatty liver disease (NAFLD) (Musso et al, 2012; Mirrakhimov and Polotsky, 2012; Mesarwi et al, 2019)
Chronic intermittent hypoxia (CIH) resulted in significant elevation in both serum alanine aminotransferase (ALT) (30.34 ± 4.97 vs. 41.30 ± 4.62 U/L, p < 0.001) and aspartate aminotransferase (AST) (45.35 ± 10.18 vs. 65.19 ± 14.62 U/L, p < 0.01) (Figures 1B,C)

Summary

Introduction

MATERIALS AND METHODSObstructive sleep apnea (OSA) is a breathing disorder characterized by intermittent nocturnal oxyhemoglobin desaturations and sleep disruption. Male gender, older age, post-menopausal state, smoking, sedative use, upper airway soft tissue abnormalities, and craniofacial changes are vital risk factors for OSA (Young et al, 2004). It has emerged as a major public health concern due to its high prevalence in mortality and morbidity (Young et al, 1993; Lindberg and Gislason, 2000; Young et al, 2008). The results suggested that OSA acted as an important risk factor for liver injury, especially non-alcoholic fatty liver disease (NAFLD) (Musso et al, 2012; Mirrakhimov and Polotsky, 2012; Mesarwi et al, 2019).

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