Detecting serum and urine metabolic profile changes of CCl4-liver fibrosis in rats at 12 weeks based on gas chromatography-mass spectrometry

Abstract

Liver fibrosis is caused by liver injury induced by a number of chronic liver diseases, including schistosome infection, hepatitis infection, metabolic disease, alcoholism and cholestasis. The tissue damage occurring after injury or inflammation of the liver is a reversible lesion; however, liver fibrosis has become a worldwide problem and poses a threat to human health. The development of an effective drug for the prevention and treatment of liver fibrosis is ongoing and uses information from different occurrences of liver fibrosis. In the present study, carbon tetrachloride (CCl4)-induced metabonomic changes in serum and urine at 12 weeks were analyzed using gas chromatography-mass spectrometry (GC/MS) to investigate potential biomarkers. Liver fibrosis was induced in rats by subcutaneous injections of CCl4 twice a week for 12 consecutive weeks. Histopathological changes were used to assess the successful production of a CCl4-induced liver fibrosis model. Serum and urine samples from the two groups were collected at 12 weeks. The metabolic profile changes were analyzed by GC/MS alongside principal component analysis and orthogonal projections to latent structures. Metabolic profile studies indicated that the clustering of the two groups could be separated and seven metabolites in serum and five metabolites in urine were identified. In serum, the metabolites identified included isoleucine, L-malic acid, α-copper, carnitine, hippuric acid, glutaric acid and glucose. In urine 2-hydroxy butyric acid, isoleucine, N-acetyl-β-alanine, cytidine and corticoid were identified. The present study demonstrated that the pathogenesis of liver fibrosis may be associated with the dysfunction of a number of metabolic pathways, including glucose, amino acid, P450, fatty acid, nucleic acid, water-electrolyte and glutathione biosynthesis. Assessing potential biomarkers may therefore provide novel targets and theories for the innovation of novel drugs to prevent and cure liver fibrosis.

A New Murine Liver Fibrosis Model Induced by Polyhexamethylene Guanidine-Phosphate

“…Furthermore, PHMG-p broadly affect metabolic pathways of lipids, which are altered in human liver fibrosis ( Diamond et al ., 2007 ) and in HSCs in vitro ( Bechmann et al ., 2009 ; Wobser et al ., 2009 ). In addition, epoxygenase P450 pathway ( Mann and Mann, 2009 ), steroid biosynthetic process ( Song et al ., 2013 ), negative regulation of gluconeogenesis ( Liu et al ., 2017 ), positive regulation of glucose metabolic process ( Nishikawa et al ., 2014 ), negative regulation of insulin secretion involved in the cellular response to glucose stimulus ( Ippolito et al ., 2016 ), arachidonic acid metabolic process ( Dong et al ., 2016 ), mitochondrion morphogenesis ( Diamond et al ., 2007 ), glucose homeostasis ( Gao et al ., 2017 ), and response to drugs ( Dong et al ., 2016 ) have been identified as liver fibrosis-related pathways in human. Many of these pathways are not affected in the existing animal fibrosis models, supporting that PHMG-p-induced liver fibrosis may be a good alternative to study human liver fibrosis.…”

Investigation of the therapeutic effect of Shaoyao Gancao decoction on CCL4‐induced liver injury in rats by metabolomic analysis

“…The decrease in glutamine level may be due to the destruction of cell membrane structure and liver malfunction caused by CCL 4 . Moreover, glutamine and alanine, the two forms of ammonia in the body, transport toxic ammonia to the liver and kidney and transform them into nontoxic compounds (Brosnan, 2003; Gao et al, 2017). Aspartate is a synthetic precursor of amino acids such as lysine and methionine.…”

“…Metabolomics, the study of small molecules, metabolites, in a biological system, has been widely used in many research fields related to human health (Gao et al, 2017). Metabolomics provides a powerful platform to simultaneously monitor endogenous metabolite levels in biological samples, including plasma, tissue, and urine, and to combine multivariate statistical analysis to reveal potential biomarkers and identify associated metabolic pathways (Jiang, Song, et al, 2017; Liang et al, 2016; Zira et al, 2013).…”

Metabolic alterations in triptolide‐induced acute hepatotoxicity

“…One study reported that increased levels of citric acid and 2-oxoglutaric acid were observed in realgar-induced hepatotoxicity, indicating that energy metabolism is disturbed after the treatment of realgar (Huo et al, 2016). Other studies revealed that disturbance of the TCA cycle could lead to an increased in the content of malic acid in rats exposed to CCl 4 (Gao et al, 2017). 2-Oxoglutaric acid is the key molecule in determining the overall rate of TCA cycle,…”