scholarly journals Hepatocytic Prominin-1 protects against liver fibrosis by stabilizing the SMAD7 protein

2019 ◽  
Author(s):  
Hyun Lee ◽  
Dong-Min Yu ◽  
Min Jee Um ◽  
Seo Yeon Yoon ◽  
Ki-Tae Kim ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Knockout Mice ◽  
Plasma Membranes ◽  
Bile Duct Ligation ◽  
Wild Type ◽  
Primary Hepatocytes ◽  
Tgfβ Signaling ◽  
Fibrotic Liver ◽  
Duct Ligation ◽  
Smad7 Protein

AbstractBackground and AimsProminin-1 (PROM1) is known to be upregulated in hepatocytic progenitor cells (HPCs) and cholangiocytes of fibrotic livers. To understand the function of upregulated PROM1 during liver fibrosis, we analyzed liver fibrosis from global and liver-specific Prom1 knockout mice and investigated the molecular mechanism of how Prom1 protects the liver against liver fibrosis.MethodsWe analyzed PROM1 expression from human liver with mild and severe liver fibrosis (n=4-9). Liver fibrosis was induced by carbon tetrachloride (CCl4) treatment and bile duct ligation (BDL) from wild type and global and liver-specific knockout mice (n=3-13). The severity of liver fibrosis was determined by qRT-PCR, immunostaining and immunoblotting for fibrotic markers such as αSMA, collagen. TGFβ signaling was also analyzed from fibrotic liver and primary hepatocytes of wild type and global and liver-specific knockout mice (n=3-5). Molecular interaction between PROM1 and SMAD7 was determined by endogenous and exogenous co-immunoprecipitation.ResultsPROM1 was found in the plasma membranes of both healthy and fibrotic hepatocytes and cholangiocytes. Global Prom1 knockout aggravated BDL- and CCl4-induced liver fibrosis. Prom1-/- hepatocytes showed increased TGFβ signaling due to reduced SMAD7 protein expression compared to that in wild-type hepatocytes. PROM1 prevented SMURF2-induced SMAD7 ubiquitination and degradation by interfering with the molecular association of SMAD7 with SMURF2. We also demonstrated that liver-specific Prom 1 knockout aggravated BDL-induced liver fibrosis due to reduced levels of SMAD7.ConclusionHepatocytic PROM1 stabilizes SMAD7, preventing TGFβ signaling. Thus, PROM1 is necessary for the negative regulation of TGFβ signaling during liver fibrosis.

LPS signaling enhances hepatic fibrogenesis caused by experimental cholestasis in mice

2006 ◽  
Vol 290 (6) ◽  
pp. G1318-G1328 ◽  
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.

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

2012 ◽  
Vol 32 (9) ◽  
pp. 1342-1353 ◽  
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

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

FEBS Letters ◽  
2007 ◽  
Vol 581 (16) ◽  
pp. 3098-3104 ◽  
Author(s):  
Hongtao Wang ◽  
Yan Zhang ◽  
Robert O. Heuckeroth
Keyword(s):  
Bile Duct ◽  
Liver Fibrosis ◽  
Bile Duct Ligation ◽  
Duct Ligation ◽  
Pai 1

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

2003 ◽  
Vol 285 (5) ◽  
pp. G1004-G1013 ◽  
Author(s):  
Zhi Zhong ◽  
Matthias Froh ◽  
Mark Lehnert ◽  
Robert Schoonhoven ◽  
Liu Yang ◽  
...  
Keyword(s):  
Bile Duct ◽  
Liver Fibrosis ◽  
Transforming Growth Factor ◽  
Bile Duct Ligation ◽  
Smooth Muscle Actin ◽  
Control Diet ◽  
Free Radical Scavengers ◽  
Bile Duct Proliferation ◽  
Duct Ligation ◽  
Experimental Cholestasis

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.

scholarly journals Cell-specific regulatory effects of CXCR2 on cholestatic liver injury

2019 ◽  
Vol 317 (6) ◽  
pp. G773-G783 ◽  
Author(s):  
Takanori Konishi ◽  
Rebecca M. Schuster ◽  
Holly S. Goetzman ◽  
Charles C. Caldwell ◽  
Alex B. Lentsch
Keyword(s):  
Bile Duct ◽  
Liver Injury ◽  
Liver Damage ◽  
Chemokine Receptor ◽  
Therapeutic Target ◽  
Bile Duct Ligation ◽  
Wild Type ◽  
Neutrophil Accumulation ◽  
Duct Ligation ◽  
Cholestatic Liver Injury

The CXC chemokine receptor 2 (CXCR2) is critical for neutrophil recruitment and hepatocellular viability but has not been studied in the context of cholestatic liver injury following bile duct ligation (BDL). The present study sought to elucidate the cell-specific roles of CXCR2 on acute liver injury after BDL. Wild-type and CXCR2−/− mice were subjected BDL. CXCR2 chimeric mice were created to assess the cell-specific role of CXCR2 on liver injury after BDL. SB225002, a selective CXCR2 antagonist, was administrated intraperitoneally after BDL to investigate the potential of pharmacological inhibition. CXCR2−/− mice had significantly less liver injury than wild-type mice at 3 and 14 days after BDL. There was no difference in biliary fibrosis among groups. The chemokines CXCL1 and CXCL2 were induced around areas of necrosis and biliary structures, respectively, both areas where neutrophils accumulated after BDL. CXCR2−/− mice showed significantly less neutrophil accumulation in those injured areas. CXCR2Liver+/Myeloid+ and CXCR2Liver−/Myeloid− mice recapitulated the wild-type and CXCR2-knockout phenotypes, respectively. CXCR2Liver+/Myeloid+ mice suffered higher liver injury than CXCR2Liver+/Myeloid− and CXCR2Liver−/Myeloid+; however, only those chimeras with knockout of myeloid CXCR2 (CXCR2Liver+/Myeloid− and CXCR2Liver−/Myeloid−) showed reduction of neutrophil accumulation around areas of necrosis. Daily administration of SB225002 starting after 3 days of BDL reduced established liver injury at 6 days. In conclusion, neutrophil CXCR2 guides the cell to the site of injury, while CXCR2 on liver cells affects liver damage independent of neutrophil accumulation. CXCR2 appears to be a viable therapeutic target for cholestatic liver injury. NEW & NOTEWORTHY This study is the first to reveal cell-specific roles of the chemokine receptor CXCR2 in cholestatic liver injury caused by bile duct ligation. CXCR2 on neutrophils facilitates neutrophil recruitment to the liver, while CXCR2 on liver cells contributes to liver damage independent of neutrophils. CXCR2 may represent a viable therapeutic target for cholestatic liver injury.

scholarly journals Increased Expression of Adherens Junction Components in Mouse Liver following Bile Duct Ligation

Biomolecules ◽  
2019 ◽  
Vol 9 (10) ◽  
pp. 636 ◽  
Author(s):  
Van Campenhout ◽  
Crespo Yanguas ◽  
Cooreman ◽  
Gijbels ◽  
Leroy ◽  
...  
Keyword(s):  
Bile Duct ◽  
Mouse Liver ◽  
Bile Duct Ligation ◽  
Adherens Junctions ◽  
Adherens Junction ◽  
Cell Junctions ◽  
Tissue Architecture ◽  
Fibrotic Liver ◽  
Protein Levels ◽  
Duct Ligation

Adherens junctions, consisting of cadherins and catenins, are a group of cell-to-cell junctions that mediate mechanistic linkage between neighboring cells. By doing so, adherens junctions ensure direct intercellular contact and play an indispensable role in maintaining tissue architecture. Considering these critical functions, it is not surprising that adherens junctions are frequently involved in disease. In the present study, the effects of bile duct ligation—a surgical procedure to experimentally induce cholestatic and fibrotic liver pathology—on hepatic adherens junctions were investigated in mice. In essence, it was found that liver mRNA and protein levels of E-cadherin, β-catenin and γ-catenin drastically increase following bile duct ligation. These results could suggest a cytoprotective role for hepatic adherens junctions following bile duct ligation.

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

2015 ◽  
Vol 308 (2) ◽  
pp. G112-G120 ◽  
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.

Paclitaxel alleviates liver fibrosis induced by bile duct ligation in rats: Role of TGF-β1, IL-10 and c-Myc

Life Sciences ◽  
2018 ◽  
Vol 211 ◽  
pp. 245-251 ◽  
Author(s):  
Maha H. Sharawy ◽  
Noha Abdel-Rahman ◽  
Nirmeen Megahed ◽  
Mohammed S. El-Awady
Keyword(s):  
Bile Duct ◽  
Liver Fibrosis ◽  
Bile Duct Ligation ◽  
Duct Ligation ◽  
Tgf Β1
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