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.2016 Sep;68(9):1203-13.
doi: 10.1111/jphp.12592. Epub 2016 Jul 1.

Chlorogenic acid inhibits cholestatic liver injury induced by α-naphthylisothiocyanate: involvement of STAT3 and NFκB signalling regulation

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Chlorogenic acid inhibits cholestatic liver injury induced by α-naphthylisothiocyanate: involvement of STAT3 and NFκB signalling regulation

Zhen Tan et al. J Pharm Pharmacol.2016 Sep.

Abstract

Objectives: Chlorogenic acid (CGA) is one of the most widely consumed polyphenols in diets and is recognized to be a natural hepatoprotective agent. Here, we evaluated the protective effect and the potential mechanism of CGA against ɑ-naphthylisothiocyanate (ANIT)-induced cholestasis and liver injury.

Methods: Twenty-five male 129/Sv mice were administered with CGA, and ANIT challenge was performed at 75 mg/kg on the 4th day. Blood was collected and subjected to biochemical analysis; the liver tissues were examined using histopathological analysis and signalling pathways.

Key findings: Chlorogenic acid almost totally attenuated the ANIT-induced liver damage and cholestasis, compared with the ANIT group. Dose of 50 mg/kg of CGA significantly prevented ANIT-induced changes in serum levels of alanine aminotransferase, alkaline phosphatases, total bile acid, direct bilirubin, indirect bilirubin (5.3-, 6.3-, 18.8-, 158-, 41.4-fold, P<0.001) and aspartate aminotransferase (4.6-fold, P<0.01). Expressions of the altered bile acid metabolism and transport-related genes were normalized by cotreatment with CGA. The expressions of interleukin 6, tumour necrosis factor-α and suppressor of cytokine signalling 3 were found to be significantly decreased (1.2-fold, ns; 11.0-fold, P<0.01; 4.4-fold, P<0.05) in the CGA/ANIT group. Western blot revealed that CGA inhibited the activation and expression of signal transducer and activator of transcription 3 and NFκB.

Conclusions: These data suggest that CGA inhibits both ANIT-induced intrahepatic cholestasis and the liver injury. This protective effect involves down-regulation of STAT3 and NFκB signalling.

Keywords: NFκB; STAT3; chlorogenic acid; cholestasis; α-naphthylisothiocyanate.

© 2016 Royal Pharmaceutical Society.

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Conflict of interest statement

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Conflict of interest

The authors declared that they have no conflicts of interest to disclose

Figures

Figure 1
Figure 1
Structure of CGA and its monitored systemic exposure level in the mice challenged with CGA 50 mg/kg for 5 days. (a) Fragmentation profile of CGA and Chemical structures of CGA. (b) The retention time and the serum concentrations of CGA after administration at 0.5, 1, 2, 5, 24 and 48 h.
Figue 2
Figue 2
Effects of CGA on the levels of serum ALT (a), AST (b), ALP (c), TBA (d), DBIL (e), IBIL (f) at 48 h after ANIT treatment in male mice. CGA was administered intragastrically once daily three 4 days prior to treatment with 75 mg/kg ANIT. Data are represented as means ± SD (n = 5; **P < 0.01; ***P < 0.001; ns, not significant).
Figure 3
Figure 3
Representative histological analysis of the livers in mice treated with ANIT and/or CGA. The patches framed in the pictures in the left column for each group were magnified pictures of the corresponding right column. CGA was administered to non-fasted mice by intragastrically once daily for 3 days prior to treatment with ANIT 75 mg/kg.
Figure 4
Figure 4
Effects of CGA expression of mRNA from genes related to bile acid metabolism and transport in mouse liver. (a) Cyp7a1, Cyp8b1, Cyp27a1 mRNA. (b) The mRNA expressions of efflux and canalicular efflux transporters. (c) mRNA expressions of basolateral uptake transporters. Data are presented as mean ± SD. Asterisks indicate statistically significant differences between vehicle/control and CGA/control or vehicle/ANIT and CGA/ANIT treated male mice (n = 5; *P < 0.05; ns, not significant).
Figure 5
Figure 5
Levels of mRNAs encoding by inflammation-related factors, apoptosis and necrosis-related factors, STAT3 target genes and LXR targrt genes. (a) c-Fos, c-Jun, Il-10, Il-6, Tnf-α. (b) Socs3, Fga, Fgb, Fgg. (c) Fas, Bcl-2, ICE. (d) Abca1, LXR, SREBP,SHP mRNAs. Data were from liver samples collected 48 h after ANIT treatment. The mRNA levels were measured by Q-PCR and normalized by 18S rRNA. Messenger RNA levels in vehicle-treated control mice were arbitrarily set as 1 and results were expressed as mean ± SD (n = 5; *P < 0.05; **P < 0.01; ns, not significant).
Figure 6
Figure 6
Western blot and densitometry analysis of STAT3 and NFκB in liver extracts. Liver samples were collected 48 h after vehicle/ANIT treatment and three of them were randomly selected for protein analysis. GAPDH was used as a loading control. The molecular weight was indicated at the left side of the respective band. (a) Western blot of STAT3 and NFκB in liver extracts. (b) Densitometry analysis of STAT3 activation in liver extracts. (c) Densitometry analysis of NFκB activation in liver extracts. Results of control group were set as 1 and data were expressed as relative intensity of p-p65 and p-STAT3 vs p65 and STAT3 respectively (n = 3; *P < 0.05; **P < 0.01; ns, not significant).
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