Polyphenols from Camellia sinenesis attenuate experimental cholestasis-induced liver fibrosis in rats

Accumulation of hydrophobic bile acids during cholestasis leads to generation of oxygen free radicals in the liver. Accordingly, this study investigated whether polyphenols from green tea Camellia sinenesis, which are potent free radical scavengers, decrease hepatic injury caused by experimental cholestasis. Rats were fed a standard chow or a diet containing 0.1% polyphenolic extracts from C. sinenesis starting 3 days before bile duct ligation. After bile duct ligation, serum alanine transaminase increased to 760 U/l after 1 day in rats fed a control diet. Focal necrosis and bile duct proliferation were also observed after 1–2 days, and fibrosis developed 2–3 wk after bile duct ligation. Additionally, procollagen-α1(I) mRNA increased 30-fold 3 wk after bile duct ligation, accompanied by increased expression of α-smooth muscle actin and transforming growth factor-β and the accumulation of 4-hydroxynenonal, an end product of lipid peroxidation. Polyphenol feeding blocked or blunted all of these bile duct ligation-dependent changes by 45–73%. Together, the results indicate that cholestasis due to bile duct ligation causes liver injury by mechanisms involving oxidative stress. Polyphenols from C. sinenesis scavenge oxygen radicals and prevent activation of stellate cells, thereby minimizing liver fibrosis.

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Positive Effects of Ger-Gen-Chyn-Lian-Tang on Cholestatic Liver Fibrosis in Bile Duct Ligation-Challenged Mice

International Journal of Molecular Sciences ◽

10.3390/ijms20174181 ◽

2019 ◽

Vol 20 (17) ◽

pp. 4181

Author(s):

Zi-Yu Chang ◽

Chin-Chang Chen ◽

Hsuan-Miao Liu ◽

Yuan-Chieh Yeh ◽

Tung-Yi Lin ◽

...

Keyword(s):

Oxidative Stress ◽

Growth Factor ◽

Bile Duct ◽

Liver Fibrosis ◽

Transforming Growth Factor ◽

Bile Duct Ligation ◽

Smooth Muscle Actin ◽

Matrix Metalloproteinase 2 ◽

Positive Effects ◽

Duct Ligation

The purpose of this study was to investigate whether Ger-Gen-Chyn-Lian-Tang (GGCLT) suppresses oxidative stress, inflammation, and angiogenesis during experimental liver fibrosis through the hypoxia-inducible factor-1α (HIF-1α)-mediated pathway. Male C57BL/6 mice were randomly assigned to a sham-control or bile duct ligation (BDL) group with or without treatment with GGCLT at 30, 100, and 300 mg/kg. Plasma alanine aminotransferase (ALT) levels were analyzed using a diagnostic kit. Liver histopathology and hepatic status parameters were measured. Compared to control mice, the BDL mice exhibited an enlargement in liver HIF-1α levels, which was suppressed by 100 and 300 mg/kg GGCLT treatments (control: BDL: BDL + GGCLT-100: BDL + GGCLT-300 = 0.95 ± 0.07: 1.95 ± 0.12: 1.43 ± 0.05: 1.12 ± 0.10 fold; p < 0.05). GGCLT restrained the induction of hepatic hydroxyproline and malondialdehyde levels in the mice challenged with BDL, further increasing the hepatic glutathione levels. Furthermore, in response to increased hepatic inflammation and fibrogenesis, significant levels of ALT, nuclear factor kappa B, transforming growth factor-β, α-smooth muscle actin, matrix metalloproteinase-2 (MMP-2), MMP-9, and procollagen-III were found in BDL mice, which were attenuated with GGCLT. In addition, GGCLT reduced the induction of angiogenesis in the liver after BDL by inhibiting vascular endothelial growth factor (VEGF) and VEGF receptors 1 and 2. In conclusion, the anti-liver fibrosis effect of GGCLT, which suppresses hepatic oxidative stress and angiogenesis, may be dependent on an HIF-1α-mediated pathway.

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LPS signaling enhances hepatic fibrogenesis caused by experimental cholestasis in mice

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00405.2005 ◽

2006 ◽

Vol 290 (6) ◽

pp. G1318-G1328 ◽

Cited By ~ 83

Author(s):

Fuyumi Isayama ◽

Ian N. Hines ◽

Michael Kremer ◽

Richard J. Milton ◽

Christy L. Byrd ◽

...

Keyword(s):

Bile Duct ◽

Liver Fibrosis ◽

Liver Injury ◽

Hepatic Fibrosis ◽

Bile Duct Ligation ◽

Wild Type ◽

Hepatic Macrophages ◽

Duct Ligation ◽

Lps Signaling ◽

Experimental Cholestasis

Although it is clear that bile acid accumulation is the major initiator of fibrosis caused by cholestatic liver disease, endotoxemia is a common side effect. However, the depletion of hepatic macrophages with gadolinium chloride blunts hepatic fibrosis. Because endotoxin is a key activator of hepatic macrophages, this study was designed to test the hypothesis that LPS signaling through CD14 contributes to hepatic fibrosis caused by experimental cholestasis. Wild-type mice and CD14 knockout mice (CD14−/−) underwent sham operation or bile duct ligation and were killed 3 wk later. Measures of liver injury, such as focal necrosis, biliary cell proliferation, and inflammatory cell influx, were not significantly different among the strains 3 wk after bile duct ligation. Markers of liver fibrosis such as Sirius red staining, liver hydroxyproline, and α-smooth muscle actin expression were blunted in CD14−/− mice compared with wild-type mice after bile duct ligation. Despite no difference in lymphocyte infiltration, the macrophage/monocyte activation marker OX42 (CD11b) and the oxidative stress/lipid peroxidation marker 4-hydroxynonenal were significantly upregulated in wild-type mice after bile duct ligation but not in CD14−/− mice. Increased profibrogenic cytokine mRNA expression in the liver after bile duct ligation was significantly blunted in CD14−/− mice compared with the wild type. The hypothesis that LPS was involved in experimental cholestatic liver fibrosis was tested using mice deficient in LPS-binding protein (LBP−/−). LBP−/− mice had less liver injury and fibrosis (Siruis red staining and hydroxyproline content) compared with wild-type mice after bile duct ligation. In conclusion, these data demonstrate that endotoxin in a CD14-dependent manner exacerbates hepatic fibrogenesis and macrophage activation to produce oxidants and cytokines after bile duct ligation.

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Faculty Opinions recommendation of A contradictory role of A1 adenosine receptor in carbon tetrachloride- and bile duct ligation-induced liver fibrosis in mice.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1345984.817085 ◽

2009 ◽

Author(s):

Jonathan A Dranoff

Keyword(s):

Carbon Tetrachloride ◽

Bile Duct ◽

Liver Fibrosis ◽

Adenosine Receptor ◽

Bile Duct Ligation ◽

A1 Adenosine Receptor ◽

Duct Ligation

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Adenoviral CCN3/NOV gene transfer fails to mitigate liver fibrosis in an experimental bile duct ligation model because of hepatocyte apoptosis

Liver International ◽

10.1111/j.1478-3231.2012.02837.x ◽

2012 ◽

Vol 32 (9) ◽

pp. 1342-1353 ◽

Cited By ~ 14

Author(s):

Erawan Borkham-Kamphorst ◽

Sebastian Huss ◽

Eddy Leur ◽

Ute Haas ◽

Ralf Weiskirchen

Keyword(s):

Bile Duct ◽

Gene Transfer ◽

Liver Fibrosis ◽

Bile Duct Ligation ◽

Hepatocyte Apoptosis ◽

Duct Ligation

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PAI-1 deficiency reduces liver fibrosis after bile duct ligation in mice through activation of tPA

FEBS Letters ◽

10.1016/j.febslet.2007.05.049 ◽

2007 ◽

Vol 581 (16) ◽

pp. 3098-3104 ◽

Cited By ~ 56

Author(s):

Hongtao Wang ◽

Yan Zhang ◽

Robert O. Heuckeroth

Keyword(s):

Bile Duct ◽

Liver Fibrosis ◽

Bile Duct Ligation ◽

Duct Ligation ◽

Pai 1

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Vitamin D inhibits development of liver fibrosis in an animal model but cannot ameliorate established cirrhosis

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00132.2013 ◽

2015 ◽

Vol 308 (2) ◽

pp. G112-G120 ◽

Cited By ~ 37

Author(s):

Shirley Abramovitch ◽

Efrat Sharvit ◽

Yosef Weisman ◽

Amir Bentov ◽

Eli Brazowski ◽

...

Keyword(s):

Vitamin D ◽

Growth Factor ◽

Bile Duct ◽

Liver Fibrosis ◽

Bile Duct Ligation ◽

Active Form ◽

Preventive Treatment ◽

Antifibrotic Effect ◽

Duct Ligation

1,25(OH)2D3, the active form of vitamin D, has an antiproliferative and antifibrotic effect on hepatic stellate cells. Our aim was to investigate the potential of 1,25(OH)2D3 to inhibit the development of liver fibrosis and to ameliorate established fibrosis in vivo. The antifibrotic effect of 1,25(OH)2D3 was investigated in a thioacetamide (TAA) model (as a preventive treatment and as a remedial treatment) and in a bile duct ligation model. In the preventive model, rats received simultaneously intraperitoneum injection of TAA and/or 1,25(OH)2D3 for 10 wk. In the remedial model, rats were treated with TAA for 10 wk and then received 1,25(OH)2D3 or saline for 8 wk. Fibrotic score was determined by Masson staining. Collagen I, α-smooth muscle actin (α-SMA), tissue inhibitor of metalloproteinase-1 (TIMP1), platelet-derived growth factor (PDGF), and transforming growth factor-β (TGF-β) expression were measured by Western blot analysis and real-time PCR. Hypercalemia was detected by chemistry measurements. Preventive treatment of 1,25(OH)2D3 significantly suppressed liver fibrosis both macroscopically and microscopically and significantly lowered the fibrotic score of the TAA + 1,25(OH)2D3 group compared with the TAA group. 1,25(OH)2D3 significantly inhibited expression of PDGF and TGF-β by ∼50% and suppressed the expression of collagen Iα1, TIMP1, and α-SMA by approximately three-, two-, and threefold, respectively. In contrast, 1,25(OH)2D3 was inefficient in amelioration of established liver fibrosis. Administration of 1,25(OH)2D3 to bile duct ligation rats led to a high mortality rate probably caused by hypercalcemia. We conclude that 1,25(OH)2D3 may be considered as a potential preventive treatment in an in vivo model but failed to ameliorate established cirrhosis.

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