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. 2018 Jul 11;18(1):112.
doi: 10.1186/s12876-018-0842-7.

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

Zhimin Liu  1 , Zhifeng Zhang  1 , Mei Huang  1 , Xiaoping Sun  2 , Bojia Liu  1 , Qiyang Guo  1 , Qingshan Chang  2 , Zhijun Duan  3
Affiliations

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

"V体育平台登录" Zhimin Liu et al. BMC Gastroenterol. .

Abstract

Background: Previous 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 VSports手机版. The present study aims to identify the specific bile acid and explore its possible mechanisms in promoting liver cirrhosis. .

Methods: Thirty 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 V体育安卓版. 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. .

Results: Concentrations 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 V体育ios版. 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. .

Conclusions: Increased 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 VSports最新版本. TCA is a potential therapeutic target for the prevention and treatment of liver cirrhosis. .

Keywords: Hepatic stellate cell; Liver cirrhosis; Metabolomics; Taurocholic acid V体育平台登录. .

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Conflict of interest statement

Ethics approval and consent to participate

This study was approved by the Ethics Committee of First Affiliated Hospital of Dalian Medical University (No:LCKY2016–34). And written informed consent was obtained from each cirrhotic patient and healthy volunteer VSports注册入口.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Normalization of original data, PCA and PLS-DA, importance in projection (VIP) analysis and cross validation of the optimal number of components of classification. a The appearance of characteristic graphical summary of data became bell-shaped distribution after a log transformation. b and c Both two dimension scores plot and three dimension scores plot of PCA indicated that there was a distinguished classification between the observation clustering of liver cirrhosis group and that of healthy control group. d and e Both two dimension scores plot and three dimension scores plot of PLS-DA indicated that there was a distinguished classification between the observation clustering of liver cirrhosis group and that of healthy control group. f and g VIP analysis of PLS-DA indicated that TCA was the most important metabolite in component one and component two. h Cross validation analysis indicated that two components model was the optimal model
Fig. 2
Fig. 2
Heatmap analysis, summary of pathway effect, compound impact on pathway and Spearman correlation. a Heatmap analysis indicated that TCA, TCDCA, TUDCA, GCA, UDCA, CDCA, CA, TLCA, TDCA, HDCA and LCA were increased in liver cirrhosis as compared with healthy controls. b Pathway analysis showed that primary bile acid biosynthesis was increased in liver cirrhosis. 1: bile acid biosynthesis. 2: taurine and hypotaurine metabolism. c Compound impact analysis implied that TCA impacted most in the increased primary bile acid biosynthesis in liver cirrhosis. d Spearman correlation analysis indicated that concentrations of TCA, GCA and TCDCA were significantly positively correlated with Child-Pugh classification (P < 0.0001). And concentrations of LCA, HDCA, CDCA, UDCA, CA, TLCA, TDCA and TUDCA were not correlated with Child-Pugh classification (P > 0.05)
Fig. 3
Fig. 3
Cell experiment. a Cell proliferation assay indicated that growth rate of LX-2 cells treated with the different concentrations of Na+/taurocholate were increased compared to that of the control group. Moreover, the effect was dose-dependent. *P < 0.05 compared with control. b and c Western blot indicated that expression of Collagen Type I and α-SMA was increased by TCA treatment as compared with the control. Moreover, effect of TCA on the expression of Collagen Type I and α-SMA was also dose-dependent. TCA50 means 50 μM Na+/taurocholate, and TCA100 means 100 μM Na+/taurocholate. *P < 0.05 compared with control. d and e Western blot indicated that the effect of TCA on Collagen Type I and TLR4 expressions in co-culture groups was more significant than that in mono-culture group. TCA50 means 50 μM Na+/taurocholate, and TCA100 means 100 μM Na+/taurocholate. *P < 0.05 compared with mono-culture group
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