Taurocholic acid is an active promoting factor, not just a biomarker of progression of liver cirrhosis: evidence from a human metabolomic study and in vitro experiments

Abstract

BackgroundPrevious studies have indicated that bile acid is associated with progression of liver cirrhosis. However, the particular role of specific bile acid in the development of liver cirrhosis is not definite. The present study aims to identify the specific bile acid and explore its possible mechanisms in promoting liver cirrhosis.MethodsThirty two cirrhotic patients and 27 healthy volunteers were enrolled. Age, gender, Child-Pugh classification and serum of patients and volunteers were collected. Liquid chromatography tandem mass spectrometry (LC-MS) was utilized to determine concentrations of 12 bile acids in serum. Principal component analysis, fold change analysis and heatmap analysis were used to identify the most changed bile acid. And pathway analysis was used to identify the most affected pathway in bile acid metabolism. Spearman rank correlation analysis was employed to assess correlation between concentrations of bile acids and Child-Pugh classification. Hepatic stellate cells (LX-2) were cultured in DMEM. LX-2 cells were also co-cultured with HepG2 cells in the transwell chambers. LX-2 cells were treated with Na+/taurocholate in different concentrations. Western blot was used to evaluate the expression of alpha smooth muscle actin (α-SMA), type I collagen, and Toll-like receptor 4 (TLR4) in LX-2 cells.ResultsConcentrations of 12 bile acids in serum of patients and healthy volunteers were determined with LC-MS successively. Principal component analysis, fold change analysis and heatmap analysis identified taurocholic acid (TCA) to be the most changed bile acid. Pathway analysis showed that TCA biosynthesis increased significantly. Spearman rank correlation analysis showed that concentration of TCA in serum of cirrhotic patients was positively associated with Child-Pugh classification. TCA increased the expression of α-SMA, type I collagen, and TLR4 in LX-2 cells. Moreover, the above effect was strengthened when LX-2 cells were co-cultured with HepG2 cells.ConclusionsIncreased TCA concentration in serum of liver cirrhotic patients is mainly due to increased bile acid biosynthesis. TCA is an active promoter of the progression of liver cirrhosis. TCA promoting liver cirrhosis is likely through activating hepatic stellate cells via upregulating TLR4 expression. TCA is a potential therapeutic target for the prevention and treatment of liver cirrhosis.

Direct and Indirect Effects of Fibroblast Growth Factor (FGF) 15 and FGF19 on Liver Fibrosis Development

“…Though the analyses above focused on BA pool size and FXR and FGFR activation in HSCs, it is important to note that various BA species have differential effects on HSCs. (31)(32)(33)(34) Of importance in this study, after treatment with CCl 4 , serum concentrations of T-CDCA and CDCA increased to a greater extent in KO mice and WT mice. Therefore, extent of FXR activation in HSCs after CCl 4 may be affected by both BA pool size and composition.…”

“…Collagen levels and Col1α1 expression were inversely correlated with TBAP size and hepatic Shp expression in KO and TG mice. Though the analyses above focused on BA pool size and FXR and FGFR activation in HSCs, it is important to note that various BA species have differential effects on HSCs . Of importance in this study, after treatment with CCl 4 , serum concentrations of T‐CDCA and CDCA increased to a greater extent in KO mice and WT mice.…”

Metabolomic and Lipidomic Biomarkers for Premalignant Liver Disease Diagnosis and Therapy

“…This was said to be due to increased synthesis. In addition, the promotion of cirrhosis progression by taurocholate was postulated to be due to stellate cell activation via the TLR4 pathway [132].…”

MitoPlex: A Targeted Multiple Reaction Monitoring Assay for Quantification of a Curated Set of Mitochondrial Proteins

“…These elevated metabolite levels are consistent with the fact that cAMP mediates the catecholaminergic control on heart rate and contractility; creatine and its degradation product creatinine are pivotal parts of the mitochondrial ATP shuttle; and L-carnitine is conjugated to fatty acids to enable their import into the mitochondria for beta-oxidation in cardiomyocytes Zaccolo, 2009;Zervou et al, 2016) . In contrast, and consistent with its distinct functions, the liver contained higher levels of taurocholic acid (liver bile salt), phenylpyruvic acid (phenylalanine metabolism restricted to liver and kidneys), phosphoenolpyruvic acid (gluconeogenesis), and riboflavin (vitamin storage) (Baker et al, 1964;Garibotto et al, 2002;Liu et al, 2018;Yang et al, 2009). Liver samples also contained higher levels of mannose, glucose-6-phosphate and galactonic acid, reflecting the differences in fuel utilization preferences between the heart (mostly fatty acids) and the liver (mix of glycolysis and fatty acid oxidation) (Rui, 2014;Stanley and Chandler, 2002;Wood et al, 1961).…”