Identification of key metabolic changes during liver fibrosis progression in rats using a urine and serum metabolomics approach

Abstract

Reversibility of hepatic fibrosis is an intrinsic response to chronic injury, and with on-going damage, fibrosis can progress to its end-stage consequence, cirrhosis. Non-invasive and reliable biomarkers for early detection of liver fibrosis are needed. Based on the CCl4-induced liver fibrosis rat model, urinary and serum metabolic profiling performed by LC-QTOF-MS associated with histological progression were utilized to identify liver fibrosis-specific potential biomarkers for early prediction and to reveal significant fibrotic pathways and their dynamic changes in different stages of liver fibrosis. Finally, nine differential metabolites in urine and ten in serum were selected and identified involving the most relevant metabolic pathways. Perturbations of tryptophan, valine, leucine, isoleucine, and citrate (TCA) cycle metabolites, along with sphingolipid and glycerophospholipid metabolites, occurred from the onset of liver fibrosis. Furthermore, dysregulation of valine and bile acid biosynthesis metabolites occurred in the intermediate and advanced stages. More importantly, among these metabolites, urinary kynurenic acid, 5-hydroxyindoleacetyl glycine, 4-(2-amino-3-hydroxyphenyl)-2,4-dioxobutanoic acid and serum sphinganine, sphingomyelin, L-leucine, L-tryptophan, and LysoPC(17:0) changed at all time points and may serve as potential early biomarkers for the diagnosis of hepatic fibrosis and as therapeutic targets. Overall, this work evaluates the potential of these metabolites for the early detection of liver fibrosis.

Lipidomic identification of plasma lipids associated with pain behaviour and pathology in a mouse model of osteoarthritis

“…The processed datasets analysed by principal component analysis (PCA) and orthogonal projections to latent structures discriminant analysis (OPLS-DA) (Trygg et al 2007) using pareto (Par) scaling. VIP (Variable Importance in the Projection) and p(corr) were used (V-Plot) to find statistically changed ions (Chang et al 2017). Ions with VIP > 1.5 and p(corr) > |0.4| were subjected to univariate analysis with False Discovery Rate (FDR) at 5% level for correction of multiple comparisons using Prism v.7 (Graph Pad, San Diego, California, USA).…”

Metabolomics discloses potential biomarkers to predict the acute HVPG response to propranolol in patients with cirrhosis

“…The fact that non‐responders showed lower NEFA levels, may reflect a lesser β‐adrenergic stimulation or a metabolic resistance of the β‐adrenoceptor that might explain that NSBB did not reach the desired effect. Glycerophospholipids have been proposed as protective agents in animal models of NASH and declining levels have been described in parallel to liver fibrosis progression . Therefore, it might be hypothesized that lower levels of glycerophospholids observed in HVPG non‐responders might be related to a more fibrogenic phenotype of cirrhosis, which could be less dependent and modifiable by vasoactive systems such as β‐adrenergic stimulation/blockade.…”

“…Glycerophospholipids have been proposed as protective agents in animal models of NASH and declining levels have been described in parallel to liver fibrosis progression. 35,36 Therefore, it might be hypothesized that lower levels of glycerophospholids observed in HVPG non-responders might be related to a more fibrogenic phenotype of cirrhosis, which could be Seventeen patients fell in the grey zone patients with cirrhosis. The analysis of these metabolites could be a useful non-invasive tool to identify these patients though further validation of the model would be desirable.…”

In vivo Antifibrotic Potential of Extracts of Acanthospermum hispidum DC. Evaluated in Wistar Rats Using Diethylnitrosamine

“…Hepatic fibrosis complicates all chronic liver diseases, whether due to chronic alcoholism, viral B or C infection, or autoimmune, biliary, parasitic or medicinal. It is now accepted that hepatic fibrosis is a dynamic process, causing not only excessive production of matrix components (fibrogenesis) [2], but also a decrease in their degradation (fibrolysis) [3].…”