Bone morphogenetic protein 4 mediates bile duct ligation induced liver fibrosis through activation of Smad1 and ERK1/2 in rat hepatic stellate cells

Hepatic stellate cells (HSCs) are involved in the pathogenesis of liver fibrosis. Resveratrol, 3,5,4′-trihydroxystilbene, is a dietary polyphenol found in natural food products. Here, we evaluated the anti-proliferative effects of a synthetic resveratrol derivative, 3,5-diethoxy-3′-hydroxyresveratrol (DEHR), on HSCs. Flow cytometry and Western blot analyses showed that DEHR induces apoptosis through the upregulation of cleaved caspase-3 and poly (ADP-ribose) polymerase expression and reduction in the level of an anti-apoptotic protein B-cell lymphoma 2 (Bcl2). As caveolin-1 (CAV1), a competitive inhibitor of heme oxygenase 1 (HO-1), is related to apoptotic proteins in hepatic cells, we focused on the role of CAV1 in DEHR-induced apoptosis in HSCs through Western blot analyses. Our results showed that the inhibitory effect of DEHR on cell viability was stronger in HO-1 siRNA-transfected cells but weakened in CAV1 siRNA-transfected cells. Collagen concentration was significantly reduced, whereas CAV1 expression increased after treatment of a bile duct ligation injury-induced liver fibrosis model with DEHR for four weeks. We confirmed that DEHR treatment significantly reduced fibrous hyperplasia around the central veins, using hematoxylin and eosin and Sirius red staining. DEHR ameliorates liver fibrosis in vitro and in vivo, possibly through a mechanism involving CAV1.

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M1567 CpG Motifs Induce Proinflammatory Events in Hepatic Stellate Cells and Are Involved in Bile Duct Ligation-Induced Hepatic Fibrosis In Vivo

Gastroenterology ◽

10.1016/s0016-5085(08)63714-2 ◽

2008 ◽

Vol 134 (4) ◽

pp. A-795

Author(s):

Erwin Gäbele ◽

Matthias Froh ◽

Reiner Wiest ◽

Florian Obermeier ◽

Jürgen Schölmerich ◽

...

Keyword(s):

Bile Duct ◽

Hepatic Fibrosis ◽

Hepatic Stellate Cells ◽

Bile Duct Ligation ◽

Stellate Cells ◽

Cpg Motifs ◽

Duct Ligation

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NOX1/nicotinamide adenine dinucleotide phosphate, reduced form (NADPH) oxidase promotes proliferation of stellate cells and aggravates liver fibrosis induced by bile duct ligation

Hepatology ◽

10.1002/hep.24465 ◽

2011 ◽

Vol 54 (3) ◽

pp. 949-958 ◽

Cited By ~ 75

Author(s):

Wenhao Cui ◽

Kuniharu Matsuno ◽

Kazumi Iwata ◽

Masakazu Ibi ◽

Misaki Matsumoto ◽

...

Keyword(s):

Bile Duct ◽

Liver Fibrosis ◽

Nadph Oxidase ◽

Nicotinamide Adenine Dinucleotide ◽

Bile Duct Ligation ◽

Nicotinamide Adenine Dinucleotide Phosphate ◽

Stellate Cells ◽

Nicotinamide Adenine ◽

Reduced Form ◽

Duct Ligation

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Faculty Opinions recommendation of NOX1/nicotinamide adenine dinucleotide phosphate, reduced form (NADPH) oxidase promotes proliferation of stellate cells and aggravates liver fibrosis induced by bile duct ligation.

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

10.3410/f.13357374.14726777 ◽

2011 ◽

Author(s):

Jonathan A Dranoff ◽

Michel Fausther ◽

Elise G Lavoie

Keyword(s):

Bile Duct ◽

Liver Fibrosis ◽

Nadph Oxidase ◽

Nicotinamide Adenine Dinucleotide ◽

Bile Duct Ligation ◽

Nicotinamide Adenine Dinucleotide Phosphate ◽

Stellate Cells ◽

Nicotinamide Adenine ◽

Reduced Form ◽

Duct Ligation

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Atorvastatin attenuates hepatic fibrosis in rats after bile duct ligation via decreased turnover of hepatic stellate cells

Journal of Hepatology ◽

10.1016/j.jhep.2010.04.025 ◽

2010 ◽

Vol 53 (4) ◽

pp. 702-712 ◽

Cited By ~ 130

Author(s):

Jonel Trebicka ◽

Martin Hennenberg ◽

Margarete Odenthal ◽

Khanwali Shir ◽

Sabine Klein ◽

...

Keyword(s):

Bile Duct ◽

Hepatic Fibrosis ◽

Hepatic Stellate Cells ◽

Bile Duct Ligation ◽

Stellate Cells ◽

Duct Ligation

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iRhom2 inhibits bile duct obstruction–induced liver fibrosis

Science Signaling ◽

10.1126/scisignal.aax1194 ◽

2019 ◽

Vol 12 (605) ◽

pp. eaax1194 ◽

Cited By ~ 7

Author(s):

Balamurugan Sundaram ◽

Kristina Behnke ◽

Andrea Belancic ◽

Mazin A. Al-Salihi ◽

Yasser Thabet ◽

...

Keyword(s):

Bile Duct ◽

Liver Fibrosis ◽

Hepatic Stellate Cells ◽

Stellate Cells ◽

Duct Ligation ◽

Tnf Α ◽

Primary Mouse ◽

Factor Α

Chronic liver disease can induce prolonged activation of hepatic stellate cells, which may result in liver fibrosis. Inactive rhomboid protein 2 (iRhom2) is required for the maturation of A disintegrin and metalloprotease 17 (ADAM17, also called TACE), which is responsible for the cleavage of membrane-bound tumor necrosis factor–α (TNF-α) and its receptors (TNFRs). Here, using the murine bile duct ligation (BDL) model, we showed that the abundance of iRhom2 and activation of ADAM17 increased during liver fibrosis. Consistent with this, concentrations of ADAM17 substrates were increased in plasma samples from mice after BDL and in patients suffering from liver cirrhosis. We observed increased liver fibrosis, accelerated disease progression, and an increase in activated stellate cells after BDL in mice lacking iRhom2 (Rhbdf2−/−) compared to that in controls. In vitro primary mouse hepatic stellate cells exhibited iRhom2-dependent shedding of the ADAM17 substrates TNFR1 and TNFR2. In vivo TNFR shedding after BDL also depended on iRhom2. Treatment of Rhbdf2−/− mice with the TNF-α inhibitor etanercept reduced the presence of activated stellate cells and alleviated liver fibrosis after BDL. Together, these data suggest that iRhom2-mediated inhibition of TNFR signaling protects against liver fibrosis.

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Increased production of ADAMTS13 in hepatic stellate cells contributes to enhanced plasma ADAMTS13 activity in rat models of cholestasis and steatohepatitis

Thrombosis and Haemostasis ◽

10.1160/th08-11-0732 ◽

2009 ◽

Vol 102 (08) ◽

pp. 389-396 ◽

Cited By ~ 14

Author(s):

Naoko Watanabe ◽

Yukio Kume ◽

Yumiko Satoh ◽

Makoto Kaneko ◽

Daiya Takai ◽

...

Keyword(s):

Smooth Muscle ◽

Bile Duct ◽

Liver Fibrosis ◽

Mrna Expression ◽

Hepatic Stellate Cells ◽

Stellate Cells ◽

Potential Contribution ◽

Adamts13 Activity ◽

Rat Models ◽

Duct Ligation

SummaryAlthough hepatic stellate cells, endothelial cells, glomerular podocytes and plateles were reported to be a source of ADAMTS13, it is not clarified which source is involved in the regulation of plasma ADAMTS13 activity. It was demonstrated previously that selective hepatic stellate cell damage in rats caused decreased plasma ADAMTS13 activity.To further elucidate the potential contribution of hepatic stellate cells to the regulation of plasma ADAMTS13 activity, this study examined plasma ADAMTS13 activity when hepatic stellate cells proliferate during the process of liver fibrosis by employing rat models of liver fibrosis due to cholestasis, bile duct ligation, and steatohepatitis, a choline-deficient L-amino acid-defined-diet. ADAMTS13 expression was increased with co-localisation with smooth muscle α-actin, a marker of hepatic stellate cells, in bile duct-ligated livers up to four weeks, in which a close correlation between ADAMTS13 and smooth muscle α-actin mRNA expressions was determined. Plasma ADAMTS13 activity, measured by a sandwich ELISA involving a specific substrate to ADAMTS13, was increased in bile duct-ligated rats with a significant correlation with ADAMTS13 mRNA expression levels in the liver. Furthermore, ADAMTS13 mRNA expression was increased with enhanced mRNA expression in smooth muscle α-actin in the livers of rats fed a choline-deficient L-amino aciddefined-diet for 16 weeks, in which increased plasma ADAMTS13 activity was determined. Thus, increased plasma ADAMTS13 activity in cholestasis and steatohepatitis in rats may be due, at least in part, to enhanced ADAMTS13 production in the liver, suggesting a significant role of hepatic stellate cells in the regulation of plasma ADAMTS13 activity.

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