The Experts below are selected from a list of 3948 Experts worldwide ranked by ideXlab platform
Nathan J Cherrington - One of the best experts on this subject based on the ideXlab platform.
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decreased apoptosis during car mediated Hepatoprotection against lithocholic acid induced liver injury in mice
Toxicology Letters, 2009Co-Authors: Lisa D Beilke, David G Besselsen, Lauren M Aleksunes, Curtis D Klaassen, Erik R Olson, Katerina Dvorak, Nathan J CherringtonAbstract:Myeloid cell leukemia-1 (Mcl-1) is an anti-apoptotic protein that is regulated by the constitutive androstane receptor (CAR). Activation of CAR can protect the liver against bile acid-induced toxicity and it may have a role in cell death via apoptosis by altering expression of Bcl-2 family proteins such as myeloid cell leukemia-1 (Mcl-1). Our aim was to determine if activation of CAR reduces hepatocellular apoptosis during cholestasis as a mechanism of Hepatoprotection. CAR+/+ (WT) and CAR−/− (CAR-null) mice were pre-treated with compounds known to activate CAR prior to induction of intrahepatic cholestasis using the secondary bile acid lithocholic acid (LCA). Pre-treatment with the CAR activators phenobarbital (PB) and TCPOBOP (TC), as well as the non-CAR activator pregnenolone 16α-carbontrile (PCN), protected against LCA-induced liver injury in WT mice, whereas liver injury was more extensive without CAR (CAR-null). Unexpectedly, expression of anti-apoptotic Mcl-1 and Bcl-xL was not increased in hepatoprotected mice. Compared to unprotected groups, apoptosis was decreased in hepatoprotected mice as evidenced by the absence of cleaved caspase 3 (cCasp3). In contrast to the cytoplasmic localization in the injured livers (LCA and oltipraz), Mcl-1 protein was localized in the nucleus of hepatoprotected livers to potentially promote cell survival. This study demonstrates that although apoptosis is reduced in hepatoprotected mice pre-treated with CAR and non-CAR activators; Hepatoprotection is not directly a result of CAR-induced Mcl-1 expression.
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constitutive androstane receptor mediated changes in bile acid composition contributes to Hepatoprotection from lithocholic acid induced liver injury in mice
Drug Metabolism and Disposition, 2009Co-Authors: Lisa D Beilke, David G Besselsen, Lauren M Aleksunes, Ricky D Holland, Rick D Beger, Curtis D Klaassen, Nathan J CherringtonAbstract:Pharmacological activation of the constitutive androstane receptor (CAR) protects the liver during cholestasis. The current study evaluates how activation of CAR influences genes involved in bile acid biosynthesis as a mechanism of Hepatoprotection during bile acid-induced liver injury. CAR activators phenobarbital (PB) and 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) or corn oil (CO) were administered to C57BL/6 wild-type (WT) and CAR knockout (CAR-null) mice before and during induction of intrahepatic cholestasis using the secondary bile acid, lithocholic acid (LCA). In LCA-treated WT and all the CAR-null groups (excluding controls), histology revealed severe multifocal necrosis. This pathology was absent in WT mice pretreated with PB and TCPOBOP, indicating CAR-dependent Hepatoprotection. Decreases in total hepatic bile acids and hepatic monohydroxy, dihydroxy, and trihydroxy bile acids in PB- and TCPOBOP-pretreated WT mice correlated with Hepatoprotection. In comparison, concentrations of monohydroxylated and dihydroxylated bile acids were increased in all the treated CAR-null mice compared with CO controls. Along with several other enzymes (Cyp7b1, Cyp27a1, Cyp39a1), Cyp8b1 expression was increased in hepatoprotected mice, which could be suggestive of a shift in the bile acid biosynthesis pathway toward the formation of less toxic bile acids. In CAR-null mice, these changes in gene expression were not different among treatment groups. These results suggest CAR mediates a shift in bile acid biosynthesis toward the formation of less toxic bile acids, as well as a decrease in hepatic bile acid concentrations. We propose that these combined CAR-mediated effects may contribute to the Hepatoprotection observed during LCA-induced liver injury.
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minimal role of hepatic transporters in the Hepatoprotection against lca induced intrahepatic cholestasis
Toxicological Sciences, 2008Co-Authors: Lisa D Beilke, David G Besselsen, Quiqiong Cheng, Supriya R Kulkarni, Angela L Slitt, Nathan J CherringtonAbstract:The multidrug resistance-associated proteins (Mrps) are a family of adenosine triphosphate-dependent transporters that facilitate the movement of various compounds, including bile acids, out of hepatocytes. The current study was conducted to determine whether induction of these transporters alters bile acid disposition as a means of Hepatoprotection during bile acid-induced cholestasis. Lithocholic acid (LCA) was used to induce intrahepatic cholestasis. C57BL/6 mice were pretreated with corn oil (CO) or known transporter inducers, phenobarbital (PB), oltipraz (OPZ), or TCPOBOP (TC) for 3 days prior to cotreatment with LCA and inducer for 4 days. Histopathology revealed that PB and TC pretreatments provide a protective effect from LCA-induced toxicity, whereas OPZ pretreatment did not. Both PB/LCA and TC/LCA cotreatment groups also had significantly lower alanine aminotransferase values than the LCA-only group. In TC/LCA cotreated mice compared with LCA only, messenger RNA (mRNA) expression of uptake transporters Ntcp and Oatp4 was significantly increased, as were sinusoidal efflux transporters Mrp3 and Mrp4. Although in PB/LCA cotreated mice, the only significant change compared with LCA-only treatment was an increase in uptake transporter Oatp4. Oatp1 was reduced in all groups compared with CO controls. No significant changes in mRNA expression were observed in Oatp2, Bsep, Mrp2, Bcrp, Mrp1, Mrp5, or Mrp6. Mrp4 protein expression was induced in the OPZ/LCA and TC/LCA cotreated groups, whereas Mrp3 protein levels remained unchanged between groups. Protein expression of Mrp1 and Mrp5 was increased in the unprotected LCA-only and OPZ/LCA mice. Thus, transporter expression did not correlate with histologic Hepatoprotection, however, there was a correlation between Hepatoprotection and significantly reduced total liver bile acids in the PB/LCA and TC/LCA cotreated mice compared with LCA only. In conclusion, changes in transporter expression did not correlate with Hepatoprotection, and therefore, transport may not play a critical role in the observed Hepatoprotection from LCA-induced cholestasis in the C57BL/6 mouse.
Saul J. Karpen - One of the best experts on this subject based on the ideXlab platform.
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stigmasterol a soy lipid derived phytosterol is an antagonist of the bile acid nuclear receptor fxr
Pediatric Research, 2007Co-Authors: Beth A. Carter, Olga A. Taylor, Daniel R. Prendergast, Tracy L. Zimmerman, David D Moore, Richard Von Furstenberg, Saul J. KarpenAbstract:Phytosterols, components of soy-derived lipids, are among the proposed exacerbants of parenteral nutrition–associated cholestasis (PNAC). We investigated whether phytosterols contribute to bile acid (BA)–induced hepatocyte damage by antagonizing a nuclear receptor (NR) critically involved in Hepatoprotection from cholestasis, FXR (farnesoid X receptor, NR1H4). In HepG2 cells, stigmasterol acetate (StigAc), a water-soluble Stig derivative, suppressed ligand-activated expression of FXR target genes involved in adaptation to cholestasis (i.e. BSEP, FGF-19, OSTα/β). Furthermore, StigAc antagonized BA-activated, FXR target genes SHP and BSEP in FXR+/+, but not in FXR−/− mouse hepatocytes. Both Stig and StigAc inhibited BA-activated, FXR-dependent reporter gene expression in transfected HepG2 cells, whereas the most prevalent phytosterol in lipids, β-sitosterol, had no inhibitory effect. Finally, among six ligand-activated NR-ligand binding domains (LBDs) tested, antagonism by StigAc was specific to only two (FXR and PXR, pregnane X receptor, NR1I2). We demonstrate that Stig, a phytosterol prevalent in soy-derived PN lipid solutions, is a potent in vitro antagonist of the NR for bile acids FXR.
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Stigmasterol, a soy lipid-derived phytosterol, is an antagonist of the bile acid nuclear receptor FXR
Pediatric Research, 2007Co-Authors: Beth A. Carter, Olga A. Taylor, Daniel R. Prendergast, Tracy L. Zimmerman, Richard Von Furstenberg, David D Moore, Saul J. KarpenAbstract:Phytosterols, components of soy-derived lipids, are among the proposed exacerbants of parenteral nutrition-associated cholestasis (PNAC). We investigated whether phytosterols contribute to bile acid (BA)-induced hepatocyte damage by antagonizing a nuclear receptor (NR) critically involved in Hepatoprotection from cholestasis, FXR (farnesoid X receptor, NR1H4). In HepG2 cells, stigmasterol acetate (StigAc), a water-soluble Stig derivative, suppressed ligand-activated expression of FXR target genes involved in adaptation to cholestasis (i.e. BSEP, FGF-19, OSTalpha/beta). Furthermore, StigAc antagonized BA-activated, FXR target genes SHP and BSEP in FXR+/+, but not in FXR-/- mouse hepatocytes. Both Stig and StigAc inhibited BA-activated, FXR-dependent reporter gene expression in transfected HepG2 cells, whereas the most prevalent phytosterol in lipids, beta-sitosterol, had no inhibitory effect. Finally, among six ligand-activated NR-ligand binding domains (LBDs) tested, antagonism by StigAc was specific to only two (FXR and PXR, pregnane X receptor, NR1I2). We demonstrate that Stig, a phytosterol prevalent in soy-derived PN lipid solutions, is a potent in vitro antagonist of the NR for bile acids FXR.
Lisa D Beilke - One of the best experts on this subject based on the ideXlab platform.
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decreased apoptosis during car mediated Hepatoprotection against lithocholic acid induced liver injury in mice
Toxicology Letters, 2009Co-Authors: Lisa D Beilke, David G Besselsen, Lauren M Aleksunes, Curtis D Klaassen, Erik R Olson, Katerina Dvorak, Nathan J CherringtonAbstract:Myeloid cell leukemia-1 (Mcl-1) is an anti-apoptotic protein that is regulated by the constitutive androstane receptor (CAR). Activation of CAR can protect the liver against bile acid-induced toxicity and it may have a role in cell death via apoptosis by altering expression of Bcl-2 family proteins such as myeloid cell leukemia-1 (Mcl-1). Our aim was to determine if activation of CAR reduces hepatocellular apoptosis during cholestasis as a mechanism of Hepatoprotection. CAR+/+ (WT) and CAR−/− (CAR-null) mice were pre-treated with compounds known to activate CAR prior to induction of intrahepatic cholestasis using the secondary bile acid lithocholic acid (LCA). Pre-treatment with the CAR activators phenobarbital (PB) and TCPOBOP (TC), as well as the non-CAR activator pregnenolone 16α-carbontrile (PCN), protected against LCA-induced liver injury in WT mice, whereas liver injury was more extensive without CAR (CAR-null). Unexpectedly, expression of anti-apoptotic Mcl-1 and Bcl-xL was not increased in hepatoprotected mice. Compared to unprotected groups, apoptosis was decreased in hepatoprotected mice as evidenced by the absence of cleaved caspase 3 (cCasp3). In contrast to the cytoplasmic localization in the injured livers (LCA and oltipraz), Mcl-1 protein was localized in the nucleus of hepatoprotected livers to potentially promote cell survival. This study demonstrates that although apoptosis is reduced in hepatoprotected mice pre-treated with CAR and non-CAR activators; Hepatoprotection is not directly a result of CAR-induced Mcl-1 expression.
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constitutive androstane receptor mediated changes in bile acid composition contributes to Hepatoprotection from lithocholic acid induced liver injury in mice
Drug Metabolism and Disposition, 2009Co-Authors: Lisa D Beilke, David G Besselsen, Lauren M Aleksunes, Ricky D Holland, Rick D Beger, Curtis D Klaassen, Nathan J CherringtonAbstract:Pharmacological activation of the constitutive androstane receptor (CAR) protects the liver during cholestasis. The current study evaluates how activation of CAR influences genes involved in bile acid biosynthesis as a mechanism of Hepatoprotection during bile acid-induced liver injury. CAR activators phenobarbital (PB) and 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) or corn oil (CO) were administered to C57BL/6 wild-type (WT) and CAR knockout (CAR-null) mice before and during induction of intrahepatic cholestasis using the secondary bile acid, lithocholic acid (LCA). In LCA-treated WT and all the CAR-null groups (excluding controls), histology revealed severe multifocal necrosis. This pathology was absent in WT mice pretreated with PB and TCPOBOP, indicating CAR-dependent Hepatoprotection. Decreases in total hepatic bile acids and hepatic monohydroxy, dihydroxy, and trihydroxy bile acids in PB- and TCPOBOP-pretreated WT mice correlated with Hepatoprotection. In comparison, concentrations of monohydroxylated and dihydroxylated bile acids were increased in all the treated CAR-null mice compared with CO controls. Along with several other enzymes (Cyp7b1, Cyp27a1, Cyp39a1), Cyp8b1 expression was increased in hepatoprotected mice, which could be suggestive of a shift in the bile acid biosynthesis pathway toward the formation of less toxic bile acids. In CAR-null mice, these changes in gene expression were not different among treatment groups. These results suggest CAR mediates a shift in bile acid biosynthesis toward the formation of less toxic bile acids, as well as a decrease in hepatic bile acid concentrations. We propose that these combined CAR-mediated effects may contribute to the Hepatoprotection observed during LCA-induced liver injury.
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minimal role of hepatic transporters in the Hepatoprotection against lca induced intrahepatic cholestasis
Toxicological Sciences, 2008Co-Authors: Lisa D Beilke, David G Besselsen, Quiqiong Cheng, Supriya R Kulkarni, Angela L Slitt, Nathan J CherringtonAbstract:The multidrug resistance-associated proteins (Mrps) are a family of adenosine triphosphate-dependent transporters that facilitate the movement of various compounds, including bile acids, out of hepatocytes. The current study was conducted to determine whether induction of these transporters alters bile acid disposition as a means of Hepatoprotection during bile acid-induced cholestasis. Lithocholic acid (LCA) was used to induce intrahepatic cholestasis. C57BL/6 mice were pretreated with corn oil (CO) or known transporter inducers, phenobarbital (PB), oltipraz (OPZ), or TCPOBOP (TC) for 3 days prior to cotreatment with LCA and inducer for 4 days. Histopathology revealed that PB and TC pretreatments provide a protective effect from LCA-induced toxicity, whereas OPZ pretreatment did not. Both PB/LCA and TC/LCA cotreatment groups also had significantly lower alanine aminotransferase values than the LCA-only group. In TC/LCA cotreated mice compared with LCA only, messenger RNA (mRNA) expression of uptake transporters Ntcp and Oatp4 was significantly increased, as were sinusoidal efflux transporters Mrp3 and Mrp4. Although in PB/LCA cotreated mice, the only significant change compared with LCA-only treatment was an increase in uptake transporter Oatp4. Oatp1 was reduced in all groups compared with CO controls. No significant changes in mRNA expression were observed in Oatp2, Bsep, Mrp2, Bcrp, Mrp1, Mrp5, or Mrp6. Mrp4 protein expression was induced in the OPZ/LCA and TC/LCA cotreated groups, whereas Mrp3 protein levels remained unchanged between groups. Protein expression of Mrp1 and Mrp5 was increased in the unprotected LCA-only and OPZ/LCA mice. Thus, transporter expression did not correlate with histologic Hepatoprotection, however, there was a correlation between Hepatoprotection and significantly reduced total liver bile acids in the PB/LCA and TC/LCA cotreated mice compared with LCA only. In conclusion, changes in transporter expression did not correlate with Hepatoprotection, and therefore, transport may not play a critical role in the observed Hepatoprotection from LCA-induced cholestasis in the C57BL/6 mouse.
Geoffrey C Farrell - One of the best experts on this subject based on the ideXlab platform.
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coffee and non alcoholic fatty liver disease brewing evidence for Hepatoprotection
Journal of Gastroenterology and Hepatology, 2014Co-Authors: Narcissus Teoh, Shaohua Chen, Shivakumar Chitturi, Geoffrey C FarrellAbstract:Coffee is one of the most popular beverages in the world. Several studies consistently show that coffee drinkers with chronic liver disease have a reduced risk of cirrhosis and a lower incidence of hepatocellular carcinoma regardless of primary etiology. With the increasing prevalence of non-alcoholic fatty liver disease (NAFLD) worldwide, there is renewed interest in the effect of coffee intake on NAFLD severity and positive clinical outcomes. This review gives an overview of growing epidemiological and clinical evidence which indicate that coffee consumption reduces severity of NAFLD. These studies vary in methodology, and potential confounding factors have not always been completely excluded. However, it does appear that coffee, and particular components other than caffeine, reduce NAFLD prevalence and inflammation of non-alcoholic steatohepatitis. Several possible mechanisms underlying coffee's hepatoprotective effects in NAFLD include antioxidative, anti-inflammatory, and antifibrotic effects, while a chemopreventive effect against hepatocarcinogenesis seems likely. The so-far limited data supporting such effects will be discussed, and the need for further study is highlighted.
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hepatic ischemia reperfusion injury pathogenic mechanisms and basis for Hepatoprotection
Journal of Gastroenterology and Hepatology, 2003Co-Authors: Narci C Teoh, Geoffrey C FarrellAbstract:This review highlights recent advances in our understanding of mechanisms underlying rep- erfusion injury to the liver after warm hepatic ischemia. Sinusoidal endothelial cells and hepatocytes are targets of injury in the early 'cytotoxic' phase, although participation of apoptosis in the cell-death pro- cess remains contentious. Kupffer cells may play an important role as the initial cytotoxic cell type and are likely a source of reactive oxygen species and proinflammatory mediators, particularly tumor necrosis factor (TNF)-a. The latter are involved with subsequent neutrophil activation and recruitment. Micro- circulatory disruption results from an imbalance between the actions of vasoconstrictors and vasodila- tors, such as nitric oxide, and also has a major impact on reperfusion injury. There is growing evidence that a brief prior ischemia-reperfusion period, termed 'ischemic preconditioning', is hepatoprotective. This can be mimicked by drugs that produce oxidative stress, and by interleukin-6 and TNF-a; both these cytokines are involved with priming hepatocytes to enter the cell cycle. Several mechanisms have been implicated including mobilization of adenosine and activation of adenosine type 2 receptors, nitric oxide, abrogation of TNF synthesis, preservation of energy metabolism, protection of the microcircu- lation and accelerated cell-cycle entry. A better understanding of preconditioning mechanisms will lead to novel approaches to improve outcomes of liver surgery. © 2003 Blackwell Publishing Asia Pty Ltd
Beth A. Carter - One of the best experts on this subject based on the ideXlab platform.
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stigmasterol a soy lipid derived phytosterol is an antagonist of the bile acid nuclear receptor fxr
Pediatric Research, 2007Co-Authors: Beth A. Carter, Olga A. Taylor, Daniel R. Prendergast, Tracy L. Zimmerman, David D Moore, Richard Von Furstenberg, Saul J. KarpenAbstract:Phytosterols, components of soy-derived lipids, are among the proposed exacerbants of parenteral nutrition–associated cholestasis (PNAC). We investigated whether phytosterols contribute to bile acid (BA)–induced hepatocyte damage by antagonizing a nuclear receptor (NR) critically involved in Hepatoprotection from cholestasis, FXR (farnesoid X receptor, NR1H4). In HepG2 cells, stigmasterol acetate (StigAc), a water-soluble Stig derivative, suppressed ligand-activated expression of FXR target genes involved in adaptation to cholestasis (i.e. BSEP, FGF-19, OSTα/β). Furthermore, StigAc antagonized BA-activated, FXR target genes SHP and BSEP in FXR+/+, but not in FXR−/− mouse hepatocytes. Both Stig and StigAc inhibited BA-activated, FXR-dependent reporter gene expression in transfected HepG2 cells, whereas the most prevalent phytosterol in lipids, β-sitosterol, had no inhibitory effect. Finally, among six ligand-activated NR-ligand binding domains (LBDs) tested, antagonism by StigAc was specific to only two (FXR and PXR, pregnane X receptor, NR1I2). We demonstrate that Stig, a phytosterol prevalent in soy-derived PN lipid solutions, is a potent in vitro antagonist of the NR for bile acids FXR.
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Stigmasterol, a soy lipid-derived phytosterol, is an antagonist of the bile acid nuclear receptor FXR
Pediatric Research, 2007Co-Authors: Beth A. Carter, Olga A. Taylor, Daniel R. Prendergast, Tracy L. Zimmerman, Richard Von Furstenberg, David D Moore, Saul J. KarpenAbstract:Phytosterols, components of soy-derived lipids, are among the proposed exacerbants of parenteral nutrition-associated cholestasis (PNAC). We investigated whether phytosterols contribute to bile acid (BA)-induced hepatocyte damage by antagonizing a nuclear receptor (NR) critically involved in Hepatoprotection from cholestasis, FXR (farnesoid X receptor, NR1H4). In HepG2 cells, stigmasterol acetate (StigAc), a water-soluble Stig derivative, suppressed ligand-activated expression of FXR target genes involved in adaptation to cholestasis (i.e. BSEP, FGF-19, OSTalpha/beta). Furthermore, StigAc antagonized BA-activated, FXR target genes SHP and BSEP in FXR+/+, but not in FXR-/- mouse hepatocytes. Both Stig and StigAc inhibited BA-activated, FXR-dependent reporter gene expression in transfected HepG2 cells, whereas the most prevalent phytosterol in lipids, beta-sitosterol, had no inhibitory effect. Finally, among six ligand-activated NR-ligand binding domains (LBDs) tested, antagonism by StigAc was specific to only two (FXR and PXR, pregnane X receptor, NR1I2). We demonstrate that Stig, a phytosterol prevalent in soy-derived PN lipid solutions, is a potent in vitro antagonist of the NR for bile acids FXR.
