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Luciano Adorini - One of the best experts on this subject based on the ideXlab platform.
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Obeticholic Acid reduces biliary and hepatic matrix metalloproteinases activity in rat hepatic ischemia reperfusion injury
PLOS ONE, 2020Co-Authors: Andrea Ferrigno, Laura Giuseppina Di Pasqua, Clarissa Berardo, Giuseppina Palladini, P Richelmi, Massimiliano Cadamuro, Luca Fabris, Stefano Perlini, Luciano AdoriniAbstract:Background We have previously shown that Obeticholic Acid (OCA) upregulates the biliary excretion of asymmetric dimethylarginine (ADMA), an inhibitor of iNOS regulating the activity of matrix metalloproteinases (MMPs). Here, the effects of OCA on MMP-2 and MMP-9 activity in liver, bile and serum were evaluated after hepatic ischemia/reperfusion (I/R) injury. Material and methods Male Wistar rats (n = 20) were orally administered 10 mg/kg/day of OCA (5 days) and subjected to a 60-min ischemia and 60-min reperfusion. Bile, serum and tissue were collected for MMP-2 and MMP-9 activity quantification. The MMP regulator tissue reversion-inducing cysteine rich protein with Kazal motifs (RECK), tissue inhibitor of metalloproteinases (TIMPs), iNOS and biliary levels of LDH, γGT, glucose and ADMA were quantified. Results In the I/R group, OCA administration reduced MMP-2 and MMP-9 in liver, bile and serum. A downregulation of tissue RECK and TIMPs, observed under I/R, were recovered by OCA. Immunohistochemical staining of hepatic tissue demonstrated that RECK expression is mainly localized in both cholangiocytes and hepatocytes. Hepatic iNOS positively correlated with tissue MMP-2 and MMP-9 activity. Biliary levels of LDH, γGT and glucose were lower in I/R rats treated with OCA; in bile, MMP levels positively correlated with LDH and γGT. Conclusion Thus, OCA administration confers protection to cholangiocytes via downregulation of biliary MMPs in livers submitted to I/R. This event is associated with hepatic RECK- and TIMP-mediated MMP decrease.
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the farnesoid x receptor agonist Obeticholic Acid upregulates biliary excretion of asymmetric dimethylarginine via mate 1 during hepatic ischemia reperfusion injury
PLOS ONE, 2018Co-Authors: Andrea Ferrigno, Luciano Adorini, Laura Giuseppina Di Pasqua, Clarissa Berardo, Veronica Siciliano, Vittoria Rizzo, P Richelmi, Mariapia VairettiAbstract:BACKGROUND: We previously showed that increased asymmetric dimethylarginine (ADMA) biliary excretion occurs during hepatic ischemia/reperfusion (I/R), prompting us to study the effects of the farnesoid X receptor (FXR) agonist Obeticholic Acid (OCA) on bile, serum and tissue levels of ADMA after I/R. MATERIAL AND METHODS: Male Wistar rats were orally administered 10mg/kg/day of OCA or vehicle for 5 days and were subjected to 60 min partial hepatic ischemia or sham-operated. After a 60 min reperfusion, serum, tissue and bile ADMA levels, liver mRNA and protein expression of ADMA transporters (CAT-1, CAT-2A, CAT-2B, OCT-1, MATE-1), and enzymes involved in ADMA synthesis (protein-arginine-N-methyltransferase-1, PRMT-1) and metabolism (dimethylarginine-dimethylaminohydrolase-1, DDAH-1) were measured. RESULTS: OCA administration induced a further increase in biliary ADMA levels both in sham and I/R groups, with no significant changes in hepatic ADMA content. A reduction in CAT-1, CAT-2A or CAT-2B transcripts was found in OCA-treated sham-operated rats compared with vehicle. Conversely, OCA administration did not change CAT-1, CAT-2A or CAT-2B expression, already reduced by I/R. However, a marked decrease in OCT-1 and increase in MATE-1 expression was observed. A similar trend occurred with protein expression. CONCLUSION: The reduced mRNA expression of hepatic CAT transporters suggests that the increase in serum ADMA levels is probably due to decreased liver uptake of ADMA from the systemic circulation. Conversely, the mechanism involved in further increasing biliary ADMA levels in sham and I/R groups treated with OCA appears to be MATE-1-dependent.
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The farnesoid X receptor agonist Obeticholic Acid upregulates biliary excretion of asymmetric dimethylarginine via MATE-1 during hepatic ischemia/reperfusion injury - Fig 8
2018Co-Authors: Andrea Ferrigno, Luciano Adorini, Laura Giuseppina Di Pasqua, Clarissa Berardo, Veronica Siciliano, Vittoria Rizzo, Plinio Richelmi, Mariapia VairettiAbstract:Schematic representation of changes in CAT-1, CAT-2A, CAT-2B, OCT-1 and MATE-1 transporters that occur in rat livers after OCA treatment (panel A) or hepatic I/R and OCA administration (panel B). CAT-1, cationic amino-Acid transporter-1; CAT-2A, cationic amino-Acid transporter-2A; CAT-2B cationic amino-Acid transporter-2B; MATE-1, multidrug and toxin extrusion protein-1; OCA, Obeticholic Acid, OCT-1, organic cation transporter-1.
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The farnesoid X receptor agonist Obeticholic Acid upregulates biliary excretion of asymmetric dimethylarginine via MATE-1 during hepatic ischemia/reperfusion injury - Fig 4
2018Co-Authors: Andrea Ferrigno, Luciano Adorini, Laura Giuseppina Di Pasqua, Clarissa Berardo, Veronica Siciliano, Vittoria Rizzo, Plinio Richelmi, Mariapia VairettiAbstract:Hepatic DDAH activity (Panel A) and mRNA expression of DDAH-1 (Panel B) at the end of reperfusion. Animals were orally administered 10 mg/kg/day of OCA in methylcellulose 1% vehicle for 5 days or with vehicle alone. Livers were submitted to 60 min ischemia followed by 60 min reperfusion. Sham-operated control animals underwent similar manipulation without vascular occlusion. Hepatic samples were collected at the end of reperfusion. The results are reported as the mean ± S.E. of 7–8 different experiments. DDAH-1, dimethylarginine dimethylaminohydrolase-1; OCA, Obeticholic Acid.
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The farnesoid X receptor agonist Obeticholic Acid upregulates biliary excretion of asymmetric dimethylarginine via MATE-1 during hepatic ischemia/reperfusion injury - Fig 3
2018Co-Authors: Andrea Ferrigno, Luciano Adorini, Laura Giuseppina Di Pasqua, Clarissa Berardo, Veronica Siciliano, Vittoria Rizzo, Plinio Richelmi, Mariapia VairettiAbstract:Hepatic protein expression of MATE-1 (Panel A), CAT-1 (Panel B), CAT-2(Panel C) and OCT-1 (Panel D) at the end of reperfusion. Animals were orally administered 10 mg/kg/day of OCA in methylcellulose 1% vehicle for 5 days or with vehicle alone. Livers were submitted to 60 min ischemia followed by 60 min reperfusion. Sham-operated control animals underwent similar manipulation without vascular occlusion. At the end of reperfusion, hepatic samples were collected. The results are reported as the mean ± S.E. of 7–8 different experiments. CAT-1, cationic amino-Acid transporter-1; CAT-2, cationic amino-Acid transporter-2; MATE-1, multidrug and toxin extrusion protein-1; OCA, Obeticholic Acid, OCT-1, organic cation transporter-1.
Andrea Ferrigno - One of the best experts on this subject based on the ideXlab platform.
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Obeticholic Acid reduces biliary and hepatic matrix metalloproteinases activity in rat hepatic ischemia reperfusion injury
PLOS ONE, 2020Co-Authors: Andrea Ferrigno, Laura Giuseppina Di Pasqua, Clarissa Berardo, Giuseppina Palladini, P Richelmi, Massimiliano Cadamuro, Luca Fabris, Stefano Perlini, Luciano AdoriniAbstract:Background We have previously shown that Obeticholic Acid (OCA) upregulates the biliary excretion of asymmetric dimethylarginine (ADMA), an inhibitor of iNOS regulating the activity of matrix metalloproteinases (MMPs). Here, the effects of OCA on MMP-2 and MMP-9 activity in liver, bile and serum were evaluated after hepatic ischemia/reperfusion (I/R) injury. Material and methods Male Wistar rats (n = 20) were orally administered 10 mg/kg/day of OCA (5 days) and subjected to a 60-min ischemia and 60-min reperfusion. Bile, serum and tissue were collected for MMP-2 and MMP-9 activity quantification. The MMP regulator tissue reversion-inducing cysteine rich protein with Kazal motifs (RECK), tissue inhibitor of metalloproteinases (TIMPs), iNOS and biliary levels of LDH, γGT, glucose and ADMA were quantified. Results In the I/R group, OCA administration reduced MMP-2 and MMP-9 in liver, bile and serum. A downregulation of tissue RECK and TIMPs, observed under I/R, were recovered by OCA. Immunohistochemical staining of hepatic tissue demonstrated that RECK expression is mainly localized in both cholangiocytes and hepatocytes. Hepatic iNOS positively correlated with tissue MMP-2 and MMP-9 activity. Biliary levels of LDH, γGT and glucose were lower in I/R rats treated with OCA; in bile, MMP levels positively correlated with LDH and γGT. Conclusion Thus, OCA administration confers protection to cholangiocytes via downregulation of biliary MMPs in livers submitted to I/R. This event is associated with hepatic RECK- and TIMP-mediated MMP decrease.
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the farnesoid x receptor agonist Obeticholic Acid upregulates biliary excretion of asymmetric dimethylarginine via mate 1 during hepatic ischemia reperfusion injury
PLOS ONE, 2018Co-Authors: Andrea Ferrigno, Luciano Adorini, Laura Giuseppina Di Pasqua, Clarissa Berardo, Veronica Siciliano, Vittoria Rizzo, P Richelmi, Mariapia VairettiAbstract:BACKGROUND: We previously showed that increased asymmetric dimethylarginine (ADMA) biliary excretion occurs during hepatic ischemia/reperfusion (I/R), prompting us to study the effects of the farnesoid X receptor (FXR) agonist Obeticholic Acid (OCA) on bile, serum and tissue levels of ADMA after I/R. MATERIAL AND METHODS: Male Wistar rats were orally administered 10mg/kg/day of OCA or vehicle for 5 days and were subjected to 60 min partial hepatic ischemia or sham-operated. After a 60 min reperfusion, serum, tissue and bile ADMA levels, liver mRNA and protein expression of ADMA transporters (CAT-1, CAT-2A, CAT-2B, OCT-1, MATE-1), and enzymes involved in ADMA synthesis (protein-arginine-N-methyltransferase-1, PRMT-1) and metabolism (dimethylarginine-dimethylaminohydrolase-1, DDAH-1) were measured. RESULTS: OCA administration induced a further increase in biliary ADMA levels both in sham and I/R groups, with no significant changes in hepatic ADMA content. A reduction in CAT-1, CAT-2A or CAT-2B transcripts was found in OCA-treated sham-operated rats compared with vehicle. Conversely, OCA administration did not change CAT-1, CAT-2A or CAT-2B expression, already reduced by I/R. However, a marked decrease in OCT-1 and increase in MATE-1 expression was observed. A similar trend occurred with protein expression. CONCLUSION: The reduced mRNA expression of hepatic CAT transporters suggests that the increase in serum ADMA levels is probably due to decreased liver uptake of ADMA from the systemic circulation. Conversely, the mechanism involved in further increasing biliary ADMA levels in sham and I/R groups treated with OCA appears to be MATE-1-dependent.
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The farnesoid X receptor agonist Obeticholic Acid upregulates biliary excretion of asymmetric dimethylarginine via MATE-1 during hepatic ischemia/reperfusion injury - Fig 8
2018Co-Authors: Andrea Ferrigno, Luciano Adorini, Laura Giuseppina Di Pasqua, Clarissa Berardo, Veronica Siciliano, Vittoria Rizzo, Plinio Richelmi, Mariapia VairettiAbstract:Schematic representation of changes in CAT-1, CAT-2A, CAT-2B, OCT-1 and MATE-1 transporters that occur in rat livers after OCA treatment (panel A) or hepatic I/R and OCA administration (panel B). CAT-1, cationic amino-Acid transporter-1; CAT-2A, cationic amino-Acid transporter-2A; CAT-2B cationic amino-Acid transporter-2B; MATE-1, multidrug and toxin extrusion protein-1; OCA, Obeticholic Acid, OCT-1, organic cation transporter-1.
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The farnesoid X receptor agonist Obeticholic Acid upregulates biliary excretion of asymmetric dimethylarginine via MATE-1 during hepatic ischemia/reperfusion injury - Fig 4
2018Co-Authors: Andrea Ferrigno, Luciano Adorini, Laura Giuseppina Di Pasqua, Clarissa Berardo, Veronica Siciliano, Vittoria Rizzo, Plinio Richelmi, Mariapia VairettiAbstract:Hepatic DDAH activity (Panel A) and mRNA expression of DDAH-1 (Panel B) at the end of reperfusion. Animals were orally administered 10 mg/kg/day of OCA in methylcellulose 1% vehicle for 5 days or with vehicle alone. Livers were submitted to 60 min ischemia followed by 60 min reperfusion. Sham-operated control animals underwent similar manipulation without vascular occlusion. Hepatic samples were collected at the end of reperfusion. The results are reported as the mean ± S.E. of 7–8 different experiments. DDAH-1, dimethylarginine dimethylaminohydrolase-1; OCA, Obeticholic Acid.
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The farnesoid X receptor agonist Obeticholic Acid upregulates biliary excretion of asymmetric dimethylarginine via MATE-1 during hepatic ischemia/reperfusion injury - Fig 3
2018Co-Authors: Andrea Ferrigno, Luciano Adorini, Laura Giuseppina Di Pasqua, Clarissa Berardo, Veronica Siciliano, Vittoria Rizzo, Plinio Richelmi, Mariapia VairettiAbstract:Hepatic protein expression of MATE-1 (Panel A), CAT-1 (Panel B), CAT-2(Panel C) and OCT-1 (Panel D) at the end of reperfusion. Animals were orally administered 10 mg/kg/day of OCA in methylcellulose 1% vehicle for 5 days or with vehicle alone. Livers were submitted to 60 min ischemia followed by 60 min reperfusion. Sham-operated control animals underwent similar manipulation without vascular occlusion. At the end of reperfusion, hepatic samples were collected. The results are reported as the mean ± S.E. of 7–8 different experiments. CAT-1, cationic amino-Acid transporter-1; CAT-2, cationic amino-Acid transporter-2; MATE-1, multidrug and toxin extrusion protein-1; OCA, Obeticholic Acid, OCT-1, organic cation transporter-1.
Mariapia Vairetti - One of the best experts on this subject based on the ideXlab platform.
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the farnesoid x receptor agonist Obeticholic Acid upregulates biliary excretion of asymmetric dimethylarginine via mate 1 during hepatic ischemia reperfusion injury
PLOS ONE, 2018Co-Authors: Andrea Ferrigno, Luciano Adorini, Laura Giuseppina Di Pasqua, Clarissa Berardo, Veronica Siciliano, Vittoria Rizzo, P Richelmi, Mariapia VairettiAbstract:BACKGROUND: We previously showed that increased asymmetric dimethylarginine (ADMA) biliary excretion occurs during hepatic ischemia/reperfusion (I/R), prompting us to study the effects of the farnesoid X receptor (FXR) agonist Obeticholic Acid (OCA) on bile, serum and tissue levels of ADMA after I/R. MATERIAL AND METHODS: Male Wistar rats were orally administered 10mg/kg/day of OCA or vehicle for 5 days and were subjected to 60 min partial hepatic ischemia or sham-operated. After a 60 min reperfusion, serum, tissue and bile ADMA levels, liver mRNA and protein expression of ADMA transporters (CAT-1, CAT-2A, CAT-2B, OCT-1, MATE-1), and enzymes involved in ADMA synthesis (protein-arginine-N-methyltransferase-1, PRMT-1) and metabolism (dimethylarginine-dimethylaminohydrolase-1, DDAH-1) were measured. RESULTS: OCA administration induced a further increase in biliary ADMA levels both in sham and I/R groups, with no significant changes in hepatic ADMA content. A reduction in CAT-1, CAT-2A or CAT-2B transcripts was found in OCA-treated sham-operated rats compared with vehicle. Conversely, OCA administration did not change CAT-1, CAT-2A or CAT-2B expression, already reduced by I/R. However, a marked decrease in OCT-1 and increase in MATE-1 expression was observed. A similar trend occurred with protein expression. CONCLUSION: The reduced mRNA expression of hepatic CAT transporters suggests that the increase in serum ADMA levels is probably due to decreased liver uptake of ADMA from the systemic circulation. Conversely, the mechanism involved in further increasing biliary ADMA levels in sham and I/R groups treated with OCA appears to be MATE-1-dependent.
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The farnesoid X receptor agonist Obeticholic Acid upregulates biliary excretion of asymmetric dimethylarginine via MATE-1 during hepatic ischemia/reperfusion injury - Fig 8
2018Co-Authors: Andrea Ferrigno, Luciano Adorini, Laura Giuseppina Di Pasqua, Clarissa Berardo, Veronica Siciliano, Vittoria Rizzo, Plinio Richelmi, Mariapia VairettiAbstract:Schematic representation of changes in CAT-1, CAT-2A, CAT-2B, OCT-1 and MATE-1 transporters that occur in rat livers after OCA treatment (panel A) or hepatic I/R and OCA administration (panel B). CAT-1, cationic amino-Acid transporter-1; CAT-2A, cationic amino-Acid transporter-2A; CAT-2B cationic amino-Acid transporter-2B; MATE-1, multidrug and toxin extrusion protein-1; OCA, Obeticholic Acid, OCT-1, organic cation transporter-1.
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The farnesoid X receptor agonist Obeticholic Acid upregulates biliary excretion of asymmetric dimethylarginine via MATE-1 during hepatic ischemia/reperfusion injury - Fig 4
2018Co-Authors: Andrea Ferrigno, Luciano Adorini, Laura Giuseppina Di Pasqua, Clarissa Berardo, Veronica Siciliano, Vittoria Rizzo, Plinio Richelmi, Mariapia VairettiAbstract:Hepatic DDAH activity (Panel A) and mRNA expression of DDAH-1 (Panel B) at the end of reperfusion. Animals were orally administered 10 mg/kg/day of OCA in methylcellulose 1% vehicle for 5 days or with vehicle alone. Livers were submitted to 60 min ischemia followed by 60 min reperfusion. Sham-operated control animals underwent similar manipulation without vascular occlusion. Hepatic samples were collected at the end of reperfusion. The results are reported as the mean ± S.E. of 7–8 different experiments. DDAH-1, dimethylarginine dimethylaminohydrolase-1; OCA, Obeticholic Acid.
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The farnesoid X receptor agonist Obeticholic Acid upregulates biliary excretion of asymmetric dimethylarginine via MATE-1 during hepatic ischemia/reperfusion injury - Fig 3
2018Co-Authors: Andrea Ferrigno, Luciano Adorini, Laura Giuseppina Di Pasqua, Clarissa Berardo, Veronica Siciliano, Vittoria Rizzo, Plinio Richelmi, Mariapia VairettiAbstract:Hepatic protein expression of MATE-1 (Panel A), CAT-1 (Panel B), CAT-2(Panel C) and OCT-1 (Panel D) at the end of reperfusion. Animals were orally administered 10 mg/kg/day of OCA in methylcellulose 1% vehicle for 5 days or with vehicle alone. Livers were submitted to 60 min ischemia followed by 60 min reperfusion. Sham-operated control animals underwent similar manipulation without vascular occlusion. At the end of reperfusion, hepatic samples were collected. The results are reported as the mean ± S.E. of 7–8 different experiments. CAT-1, cationic amino-Acid transporter-1; CAT-2, cationic amino-Acid transporter-2; MATE-1, multidrug and toxin extrusion protein-1; OCA, Obeticholic Acid, OCT-1, organic cation transporter-1.
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Hepatic iNOS and eNOS at the end of reperfusion.
2018Co-Authors: Andrea Ferrigno, Luciano Adorini, Laura Giuseppina Di Pasqua, Clarissa Berardo, Veronica Siciliano, Vittoria Rizzo, Plinio Richelmi, Mariapia VairettiAbstract:Animals were orally administered 10 mg/kg/day of OCA in methylcellulose 1% vehicle for 5 days or with vehicle alone. Livers were submitted to 60 min ischemia followed by 60 min reperfusion. Sham-operated control animals underwent similar manipulation without vascular occlusion. Hepatic samples were collected at the end of reperfusion. The results are reported as the mean ± S.E. of 7–8 different experiments. OCA, Obeticholic Acid.
Frederik Nevens - One of the best experts on this subject based on the ideXlab platform.
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improved markers of cholestatic liver injury in patients with primary biliary cholangitis treated with Obeticholic Acid and bezafibrate
Hepatology, 2020Co-Authors: Lena Smets, Jef Verbeek, Hannelie Korf, Schalk Van Der Merwe, Frederik NevensAbstract:A decrease or normalization of alkaline phosphatase (ALP) and bilirubin levels in patients treated for primary biliary cholangitis (PBC) predicts a better survival. Obeticholic Acid (OCA) is the approved second-line therapy if ursodeoxycholic Acid (UCDA) fails, but its use may worsen pruritus. Adding bezafibrate to UCDA improved biochemical markers of cholestatic liver injury and decreased pruritus severity. Because normalization of ALP and bilirubin was only achieved in a minority of patients in these studies, we explored whether bezafibrate (off-label drug) could improve the effect of OCA (licensed drug) on cholestasis.
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OCA improves 7-day survival after intestinal IRI.
2017Co-Authors: Laurens J. Ceulemans, Frederik Nevens, Len Verbeke, Ricard Farre, Jean-paul Decuypere, Gert De Hertogh, Kaatje Lenaerts, Ina Jochmans, Diethard Monbaliu, Jan TackAbstract:OCA: Obeticholic Acid; IRI: ischemia reperfusion injury. n = 10/group, log-rank: p = 0.0128.
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a placebo controlled trial of Obeticholic Acid in primary biliary cholangitis
The New England Journal of Medicine, 2016Co-Authors: Frederik Nevens, Pietro Andreone, G Mazzella, Simone I Strasser, Christopher L Bowlus, Pietro Invernizzi, J P H Drenth, Paul J Pockros, Jaroslaw Regula, Ulrich BeuersAbstract:Background Primary biliary cholangitis (formerly called primary biliary cirrhosis) can progress to cirrhosis and death despite ursodiol therapy. Alkaline phosphatase and bilirubin levels correlate with the risk of liver transplantation or death. Obeticholic Acid, a farnesoid X receptor agonist, has shown potential benefit in patients with this disease. Methods In this 12-month, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 217 patients who had an inadequate response to ursodiol or who found the side effects of ursodiol unacceptable to receive Obeticholic Acid at a dose of 10 mg (the 10-mg group), Obeticholic Acid at a dose of 5 mg with adjustment to 10 mg if applicable (the 5-10-mg group), or placebo. The primary end point was an alkaline phosphatase level of less than 1.67 times the upper limit of the normal range, with a reduction of at least 15% from baseline, and a normal total bilirubin level. Results Of 216 patients who underwent randomization and received at least one dose of Obeticholic Acid or placebo, 93% received ursodiol as background therapy. The primary end point occurred in more patients in the 5-10-mg group (46%) and the 10-mg group (47%) than in the placebo group (10%; P Conclusions Obeticholic Acid administered with ursodiol or as monotherapy for 12 months in patients with primary biliary cholangitis resulted in decreases from baseline in alkaline phosphatase and total bilirubin levels that differed significantly from the changes observed with placebo. There were more serious adverse events with Obeticholic Acid. (Funded by Intercept Pharmaceuticals; POISE ClinicalTrials.gov number, NCT01473524; Current Controlled Trials number, ISRCTN89514817.).
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Obeticholic Acid a farnesoid x receptor agonist improves portal hypertension by two distinct pathways in cirrhotic rats
Hepatology, 2014Co-Authors: Len Verbeke, Ricard Farre, Tim Vanuytsel, Mina Komuta, Tania Roskams, Jonel Trebicka, S Klein, Ingrid Vander Elst, Petra Windmolders, Frederik NevensAbstract:The farnesoid X receptor (FXR) is a nuclear bile Acid receptor involved in bile Acid homeostasis, hepatic and intestinal inflammation, liver fibrosis, and cardiovascular disease. We studied the effect of short-term treatment with Obeticholic Acid (INT-747), a potent selective FXR agonist, on intrahepatic hemodynamic dysfunction and signaling pathways in different rat models of cirrhotic portal hypertension (PHT). For this, thioacetamide (TAA)-intoxicated and bile-duct–ligated (BDL) rats were used as models. After gavage of two doses of 30 mg/kg of INT-747 or vehicle within 24 hours, in vivo hemodynamics were assessed. Additionally, we evaluated the direct effect of INT-747 on total intrahepatic vascular resistance (IHVR) and intrahepatic vascular tone (endothelial dysfunction and hyperresponsiveness to methoxamine) by means of an in situ liver perfusion system and on hepatic stellate cell contraction in vitro. FXR expression and involved intrahepatic vasoactive pathways (e.g., endothelial nitric oxide synthase [eNOS], Rho-kinase, and dimethylarginine dimethylaminohydrolase [DDAH]) were analyzed by immunohistochemistry, reverse-transcriptase polymerase chain reaction, or western blotting. In both cirrhotic models, FXR expression was decreased. Treatment with INT-747 in TAA and BDL reactivated the FXR downstream signaling pathway and decreased portal pressure by lowering total IHVR without deleterious systemic hypotension. In the perfused TAA and BDL cirrhotic liver, INT-747 improved endothelial vasorelaxation capacity, but not hyperresponsiveness. In both groups, this was associated with an increased eNOS activity, which, in TAA, related to down-regulation of Rho-kinase and in BDL to up-regulation of DDAH-2. Conclusion: FXR agonist INT-747 improves PHT in two different rat models of cirrhosis by decreasing IHVR. This hemodynamic effect relates to increased intrahepatic eNOS activity by pathways that differ depending on the etiology of cirrhosis. (Hepatology 2014;59:2286–2298)
Laura Giuseppina Di Pasqua - One of the best experts on this subject based on the ideXlab platform.
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Obeticholic Acid reduces biliary and hepatic matrix metalloproteinases activity in rat hepatic ischemia reperfusion injury
PLOS ONE, 2020Co-Authors: Andrea Ferrigno, Laura Giuseppina Di Pasqua, Clarissa Berardo, Giuseppina Palladini, P Richelmi, Massimiliano Cadamuro, Luca Fabris, Stefano Perlini, Luciano AdoriniAbstract:Background We have previously shown that Obeticholic Acid (OCA) upregulates the biliary excretion of asymmetric dimethylarginine (ADMA), an inhibitor of iNOS regulating the activity of matrix metalloproteinases (MMPs). Here, the effects of OCA on MMP-2 and MMP-9 activity in liver, bile and serum were evaluated after hepatic ischemia/reperfusion (I/R) injury. Material and methods Male Wistar rats (n = 20) were orally administered 10 mg/kg/day of OCA (5 days) and subjected to a 60-min ischemia and 60-min reperfusion. Bile, serum and tissue were collected for MMP-2 and MMP-9 activity quantification. The MMP regulator tissue reversion-inducing cysteine rich protein with Kazal motifs (RECK), tissue inhibitor of metalloproteinases (TIMPs), iNOS and biliary levels of LDH, γGT, glucose and ADMA were quantified. Results In the I/R group, OCA administration reduced MMP-2 and MMP-9 in liver, bile and serum. A downregulation of tissue RECK and TIMPs, observed under I/R, were recovered by OCA. Immunohistochemical staining of hepatic tissue demonstrated that RECK expression is mainly localized in both cholangiocytes and hepatocytes. Hepatic iNOS positively correlated with tissue MMP-2 and MMP-9 activity. Biliary levels of LDH, γGT and glucose were lower in I/R rats treated with OCA; in bile, MMP levels positively correlated with LDH and γGT. Conclusion Thus, OCA administration confers protection to cholangiocytes via downregulation of biliary MMPs in livers submitted to I/R. This event is associated with hepatic RECK- and TIMP-mediated MMP decrease.
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the farnesoid x receptor agonist Obeticholic Acid upregulates biliary excretion of asymmetric dimethylarginine via mate 1 during hepatic ischemia reperfusion injury
PLOS ONE, 2018Co-Authors: Andrea Ferrigno, Luciano Adorini, Laura Giuseppina Di Pasqua, Clarissa Berardo, Veronica Siciliano, Vittoria Rizzo, P Richelmi, Mariapia VairettiAbstract:BACKGROUND: We previously showed that increased asymmetric dimethylarginine (ADMA) biliary excretion occurs during hepatic ischemia/reperfusion (I/R), prompting us to study the effects of the farnesoid X receptor (FXR) agonist Obeticholic Acid (OCA) on bile, serum and tissue levels of ADMA after I/R. MATERIAL AND METHODS: Male Wistar rats were orally administered 10mg/kg/day of OCA or vehicle for 5 days and were subjected to 60 min partial hepatic ischemia or sham-operated. After a 60 min reperfusion, serum, tissue and bile ADMA levels, liver mRNA and protein expression of ADMA transporters (CAT-1, CAT-2A, CAT-2B, OCT-1, MATE-1), and enzymes involved in ADMA synthesis (protein-arginine-N-methyltransferase-1, PRMT-1) and metabolism (dimethylarginine-dimethylaminohydrolase-1, DDAH-1) were measured. RESULTS: OCA administration induced a further increase in biliary ADMA levels both in sham and I/R groups, with no significant changes in hepatic ADMA content. A reduction in CAT-1, CAT-2A or CAT-2B transcripts was found in OCA-treated sham-operated rats compared with vehicle. Conversely, OCA administration did not change CAT-1, CAT-2A or CAT-2B expression, already reduced by I/R. However, a marked decrease in OCT-1 and increase in MATE-1 expression was observed. A similar trend occurred with protein expression. CONCLUSION: The reduced mRNA expression of hepatic CAT transporters suggests that the increase in serum ADMA levels is probably due to decreased liver uptake of ADMA from the systemic circulation. Conversely, the mechanism involved in further increasing biliary ADMA levels in sham and I/R groups treated with OCA appears to be MATE-1-dependent.
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The farnesoid X receptor agonist Obeticholic Acid upregulates biliary excretion of asymmetric dimethylarginine via MATE-1 during hepatic ischemia/reperfusion injury - Fig 8
2018Co-Authors: Andrea Ferrigno, Luciano Adorini, Laura Giuseppina Di Pasqua, Clarissa Berardo, Veronica Siciliano, Vittoria Rizzo, Plinio Richelmi, Mariapia VairettiAbstract:Schematic representation of changes in CAT-1, CAT-2A, CAT-2B, OCT-1 and MATE-1 transporters that occur in rat livers after OCA treatment (panel A) or hepatic I/R and OCA administration (panel B). CAT-1, cationic amino-Acid transporter-1; CAT-2A, cationic amino-Acid transporter-2A; CAT-2B cationic amino-Acid transporter-2B; MATE-1, multidrug and toxin extrusion protein-1; OCA, Obeticholic Acid, OCT-1, organic cation transporter-1.
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The farnesoid X receptor agonist Obeticholic Acid upregulates biliary excretion of asymmetric dimethylarginine via MATE-1 during hepatic ischemia/reperfusion injury - Fig 4
2018Co-Authors: Andrea Ferrigno, Luciano Adorini, Laura Giuseppina Di Pasqua, Clarissa Berardo, Veronica Siciliano, Vittoria Rizzo, Plinio Richelmi, Mariapia VairettiAbstract:Hepatic DDAH activity (Panel A) and mRNA expression of DDAH-1 (Panel B) at the end of reperfusion. Animals were orally administered 10 mg/kg/day of OCA in methylcellulose 1% vehicle for 5 days or with vehicle alone. Livers were submitted to 60 min ischemia followed by 60 min reperfusion. Sham-operated control animals underwent similar manipulation without vascular occlusion. Hepatic samples were collected at the end of reperfusion. The results are reported as the mean ± S.E. of 7–8 different experiments. DDAH-1, dimethylarginine dimethylaminohydrolase-1; OCA, Obeticholic Acid.
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The farnesoid X receptor agonist Obeticholic Acid upregulates biliary excretion of asymmetric dimethylarginine via MATE-1 during hepatic ischemia/reperfusion injury - Fig 3
2018Co-Authors: Andrea Ferrigno, Luciano Adorini, Laura Giuseppina Di Pasqua, Clarissa Berardo, Veronica Siciliano, Vittoria Rizzo, Plinio Richelmi, Mariapia VairettiAbstract:Hepatic protein expression of MATE-1 (Panel A), CAT-1 (Panel B), CAT-2(Panel C) and OCT-1 (Panel D) at the end of reperfusion. Animals were orally administered 10 mg/kg/day of OCA in methylcellulose 1% vehicle for 5 days or with vehicle alone. Livers were submitted to 60 min ischemia followed by 60 min reperfusion. Sham-operated control animals underwent similar manipulation without vascular occlusion. At the end of reperfusion, hepatic samples were collected. The results are reported as the mean ± S.E. of 7–8 different experiments. CAT-1, cationic amino-Acid transporter-1; CAT-2, cationic amino-Acid transporter-2; MATE-1, multidrug and toxin extrusion protein-1; OCA, Obeticholic Acid, OCT-1, organic cation transporter-1.
