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Study of NMR-spectroscopy-based Liver Metabonomics of Hyperhomocysteinemia of Rat Following Restraint Stress

Author: WangYongQin
Tutor: YaoLin;QianLingJia;ZhangYanShu;HanGang
School: North China Coal Medical
Course: Health Toxicology
Keywords: restraint stress hyperhomocysteinemia metabonomics liver extracts 1~H-NMR Principal component analysis(PCA)
CLC: R363
Type: Master's thesis
Year: 2009
Downloads: 44
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Objectives In present study, we established the rats hyperhomocysteinemia model to explore the changes of liver metabolism of rats with Hyperhomocysteinemia, and further reveal the mechanism of the liver metabolic disorders caused by the body’s increased homocysteine as well as search for metabolic markers and interesting target .Methods The animal model was induced by chronic restraint stress according to the method of Galea et al, with slight modifications. Thirty adult male Wistar rats weighing 180~200g were divided randomly into control and stress groups. All rats were housed in a pathogen-free environment at room temperature (RT: 22–25°C) and maintained on rat chow and tap water ad libitum before restraint stress. Individual rats in the stressed group were placed in a specially built size-manipulable cabin for 6h/day (from 9:00 am to 15:00 pm) for 1, 2, 4, 6 and 8 weeks respectively, and control rats were not disturbed during that period. Rats were sacrificed 24 hours after the last day of restraint. Liver were rapidly excised, immersed into ice-cold PBS buffer, and washed three times. After washing, the livers were cut into large pieces, weighed and minced into 1-2 mm3 pieces, and immediately frozen in liquid nitrogen.Rat liver metabolites were detected using 1~H-NMR and samples compared to the rat liver tissue extracts of water-soluble and fat-soluble extract of the metabolic model of normal control group and stress group with principal component analysis (PCA), and we establish a stable technology platform of liver tissue metabolism.Base on our established technique platform, We further explore the impact of mice age and stress intensity on the difference mode of liver metabolism and metabolic status. According to factor loading map (loading plot) ,the literature and database, we search out and assay a large quantity of small molecule metabolism which really impact the changes of metabolic pattern. We analyze metabolic pathways of these small molecules in order to explore the mechanism of these small molecules when the body occur to the liver metabolic disorders, as well as reciprocity of hyperhomocysteinemia.Results The finding shown that restraint stress may lead to homocysteine increase in rat plasma. The hyperhomocysteinemia in animal models were successfully established through the method of restraint stress. A high repeatability and high resolution of rat liver tissue extract of metabolomics research methods was also establish at the same time. By comparing 1~H-NMR spectra and PCA analysis between control and stress models we found that there is significant difference in term of rat liver metabolism pattern between the different strength stress rat model in As our expected the metabolic component can also be distinguished. 24 kinds of small molecule metabolic content were changed in the water-soluble extract of rat liver tissue; and 14 kinds of small molecule metabolic content were changed in fat-soluble extract. All above described changes of the metabolic components indicated that restraint stress led to glycolysis、gluconeogenesis capacity、tricarboxylic acid cycle as well as the disorder of lipid metabolism disordered. Liver Metabolic disorders were related to mitochondria、endoplasmic reticulum dysfunction and oxidative phosphorylation and lipid oxidation amean while the antioxidant defense system of liver were damaged too.Conclusions Restraint stress results in the occurrence of rats hyperhomocysteinemia. Changes of the liver metabolic status were found by the 1~H-NMR detection and PCA analysis. At the sam time we found that the rat liver metabolism phenotype is also significant changes along with the increase of stress intensity. Small molecules (amino acids, the chemical structure fragment of fat-soluble) which is assayed for metabolic phenotype changes to becontributed greatly, contribute to a tremendous impact for the body hyperhomocysteinemia energy metabolism which is caused by restraint stress. This study shows that NMR-based metabonomics study of technology is an ideal instrument which is the understanding of metabolism status and etiology, with bright prospects for development

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