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  • 1
    Online Resource
    Online Resource
    H1-antihistamines exacerbate high-fat diet-induced hepatic steatosis in wild-type but not in apolipoprotein E knockout mice
    American Physiological Society ; 2014
    In:  American Journal of Physiology-Gastrointestinal and Liver Physiology Vol. 307, No. 2 ( 2014-07-15), p. G219-G228
    Details
    In: American Journal of Physiology-Gastrointestinal and Liver Physiology, American Physiological Society, Vol. 307, No. 2 ( 2014-07-15), p. G219-G228
    Abstract: We examined the effects of two over-the-counter H1-antihistamines on the progression of fatty liver disease in male C57Bl/6 wild-type and apolipoprotein E (ApoE)−/− mice. Mice were fed a high-fat diet (HFD) for 3 mo, together with administration of either cetirizine (4 mg/kg body wt) or fexofenadine (40 mg/kg body wt) in drinking water. Antihistamine treatments increased body weight gain, gonadal fat deposition, liver weight, and hepatic steatosis in wild-type mice but not in ApoE−/− mice. Lobular inflammation, acute inflammation, and necrosis were not affected by H1-antihistamines in either genotype. Serum biomarkers of liver injury tended to increase in antihistamine-treated wild-type mice. Serum level of glucose was increased by fexofenadine, whereas lipase was increased by cetirizine. H1-antihistamines reduced the mRNA expression of ApoE and carbohydrate response element-binding protein in wild-type mice, without altering the mRNA expression of sterol regulatory element-binding protein 1c, fatty acid synthase, or ApoB100, in either genotype. Fexofenadine increased both triglycerides and cholesterol ester, whereas cetirizine increased only cholesterol ester in liver, with a concomitant decrease in serum triglycerides by both antihistamines in wild-type mice. Antihistamines increased hepatic levels of conjugated bile acids in wild-type mice, with the effect being significant in fexofenadine-treated animals. The increase was associated with changes in the expression of organic anion transport polypeptide 1b2 and bile salt export pump. These results suggest that H1-antihistamines increase the progression of fatty liver disease in wild-type mice, and there seems to be an association between the severity of disease, presence of ApoE, and increase in hepatic bile acid levels.
    Type of Medium: Online Resource
    ISSN: 0193-1857 , 1522-1547
    URL: Article
    DOI: 10.1152/ajpgi.00027.2014
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2014
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  • 2
    Online Resource
    Online Resource
    Tissue factor-dependent coagulation contributes to α-naphthylisothiocyanate-induced cholestatic liver injury in mice
    American Physiological Society ; 2009
    In:  American Journal of Physiology-Gastrointestinal and Liver Physiology Vol. 296, No. 4 ( 2009-04), p. G840-G849
    Details
    In: American Journal of Physiology-Gastrointestinal and Liver Physiology, American Physiological Society, Vol. 296, No. 4 ( 2009-04), p. G840-G849
    Abstract: Separation of concentrated bile acids from hepatic parenchymal cells is a key function of the bile duct epithelial cells (BDECs) that form intrahepatic bile ducts. Using coimmunostaining, we found that tissue factor (TF), the principal activator of coagulation, colocalized with cytokeratin 19, a marker of BDECs in the adult mouse liver. BDEC injury induced by xenobiotics such as α-naphthylisothiocyanate (ANIT) causes cholestasis, inflammation, and hepatocellular injury. We tested the hypothesis that acute ANIT-induced cholestatic hepatitis is associated with TF-dependent activation of coagulation and determined the role of TF in ANIT hepatotoxicity. Treatment of mice with ANIT (60 mg/kg) caused multifocal hepatic necrosis and significantly increased serum biomarkers of cholestasis and hepatic parenchymal cell injury. ANIT treatment also significantly increased liver TF expression and activity. ANIT-induced activation of the coagulation cascade was shown by increased plasma thrombin-antithrombin levels and significant deposition of fibrin within the necrotic foci. ANIT-induced coagulation and liver injury were reduced in low-TF mice, which express 1% of normal TF levels. The results indicate that ANIT-induced liver injury is accompanied by TF-dependent activation of the coagulation cascade and that TF contributes to the progression of injury during acute cholestatic hepatitis.
    Type of Medium: Online Resource
    ISSN: 0193-1857 , 1522-1547
    URL: Article
    DOI: 10.1152/ajpgi.90639.2008
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2009
    detail.hit.zdb_id: 1477329-6
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  • 3
    Online Resource
    Online Resource
    Mechanisms of STAT3 activation in the liver of FXR knockout mice
    American Physiological Society ; 2013
    In:  American Journal of Physiology-Gastrointestinal and Liver Physiology Vol. 305, No. 11 ( 2013-12-01), p. G829-G837
    Details
    In: American Journal of Physiology-Gastrointestinal and Liver Physiology, American Physiological Society, Vol. 305, No. 11 ( 2013-12-01), p. G829-G837
    Abstract: Farnesoid X receptor (FXR, Nr1h4) is a ligand-activated transcription factor belonging to the nuclear receptor superfamily. FXR is essential in maintaining bile acid (BA) homeostasis, and FXR −/− mice develop cholestasis, inflammation, and spontaneous liver tumors. The signal transducer and activator of transcription 3 (STAT3) is well known to regulate liver growth, and STAT3 is feedback inhibited by its target gene, the suppressor of cytokine signaling 3 (SOCS3). Strong activation of STAT3 was detected in FXR −/− mouse livers. However, the mechanism of STAT3 activation with FXR deficiency remains elusive. Wild-type (WT) and FXR −/− mice were used to detect STAT3 pathway activation in the liver. In vivo BA feeding or deprivation was used to determine the role of BAs in STAT3 activation, and in vitro molecular approaches were used to determine the direct transcriptional regulation of SOCS3 by FXR. STAT3 was activated in FXR −/− but not WT mice. BA feeding increased, but deprivation by cholestyramine reduced, serum inflammatory markers and STAT3 activation. Furthermore, the Socs3 gene was determined as a direct FXR target gene. The elevated BAs and inflammation, along with reduced SOCS3, collectively contribute to the activation of the STAT3 signaling pathway in the liver of FXR −/− mice. This study suggests that the constitutive activation of STAT3 may be a mechanism of liver carcinogenesis in FXR −/− mice.
    Type of Medium: Online Resource
    ISSN: 0193-1857 , 1522-1547
    URL: Article
    DOI: 10.1152/ajpgi.00155.2013
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2013
    detail.hit.zdb_id: 1477329-6
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  • 4
    Online Resource
    Online Resource
    Mice with hepatocyte-specific FXR deficiency are resistant to spontaneous but susceptible to cholic acid-induced hepatocarcinogenesis
    American Physiological Society ; 2016
    In:  American Journal of Physiology-Gastrointestinal and Liver Physiology Vol. 310, No. 5 ( 2016-03-01), p. G295-G302
    Details
    In: American Journal of Physiology-Gastrointestinal and Liver Physiology, American Physiological Society, Vol. 310, No. 5 ( 2016-03-01), p. G295-G302
    Abstract: Farnesoid X receptor (FXR) belongs to the nuclear receptor superfamily with its endogenous ligands bile acids. Mice with whole body FXR deficiency develop liver tumors spontaneously, but the underlying mechanism is unclear. Moreover, it is unknown whether FXR deficiency in liver alone serves as a tumor initiator or promoter during liver carcinogenesis. This study aims to evaluate the effects of hepatocyte-specific FXR deficiency (FXR hep−/− ) in liver tumor formation. The results showed that FXR hep−/− mice did not show spontaneous liver tumorigenesis with aging (up to 24 mo of age). Therefore FXR hep−/− mice were fed a bile acid (cholic acid)-containing diet alone or along with a liver tumor initiator, diethylnitrosamine (DEN). Thirty weeks later, no tumors were found in wild-type or FXR hep−/− mice without any treatment or with DEN only. However, with cholic acid, while only some wild-type mice developed tumors, all FXR hep−/− mice presented with severe liver injury and tumors. Interestingly, FXR hep−/− mouse livers increased basal expression of tumor suppressor p53 protein, apoptosis, and decreased basal cyclin D1 expression, which may prevent tumor development in FXR hep−/− mice. However, cholic acid feeding reversed these effects in FXR hep−/− mice, which is associated with an increased cyclin D1 and decreased cell cycle inhibitors. More in-depth analysis indicates that the increased in cell growth might result from disturbance of the MAPK and JAK/Stat3 signaling pathways. In conclusion, this study shows that hepatic FXR deficiency may only serve as a tumor initiator, and increased bile acids is required for tumor formation likely by promoting cell proliferation.
    Type of Medium: Online Resource
    ISSN: 0193-1857 , 1522-1547
    URL: Article
    DOI: 10.1152/ajpgi.00134.2015
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2016
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  • 5
    Online Resource
    Online Resource
    Role of the blood coagulation cascade in hepatic fibrosis
    American Physiological Society ; 2018
    In:  American Journal of Physiology-Gastrointestinal and Liver Physiology Vol. 315, No. 2 ( 2018-08-01), p. G171-G176
    Details
    In: American Journal of Physiology-Gastrointestinal and Liver Physiology, American Physiological Society, Vol. 315, No. 2 ( 2018-08-01), p. G171-G176
    Abstract: Liver is the primary source of numerous proteins that are critical for normal function of the blood coagulation cascade. Because of this, diseases of the liver, particularly when affiliated with severe complications like cirrhosis, are associated with abnormalities of blood clotting. Although conventional interpretation has inferred cirrhosis as a disorder of uniform bleeding risk, it is now increasingly appreciated as a disease wherein the coagulation cascade is precariously rebalanced. Moreover, prothrombotic risk factors are also associated with a more rapid progression of fibrosis in humans, suggesting that coagulation proteases participate in disease pathogenesis. Indeed, strong evidence drawn from experimental animal studies indicates that components of the coagulation cascade, particularly coagulation factor Xa and thrombin, drive profibrogenic events, leading to hepatic fibrosis. Here, we concisely review the evidence supporting a pathologic role for coagulation in the development of liver fibrosis and the potential mechanisms involved. Further, we highlight how studies in experimental animals may shed light on emerging clinical evidence, suggesting that beneficial effects of anticoagulation could extend beyond preventing thrombotic complications to include reducing pathologies like fibrosis.
    Type of Medium: Online Resource
    ISSN: 0193-1857 , 1522-1547
    URL: Article
    DOI: 10.1152/ajpgi.00402.2017
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2018
    detail.hit.zdb_id: 1477329-6
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