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Karpen S.J.,Texas Childrens Liver Center | Trauner M.,Laboratory of Experimental and Molecular Hepatology
Journal of Hepatology | Year: 2010

A joint EASL/AASLD Monothematic Conference on 'Nuclear Receptors and Liver Disease' was held from February 27th to March 1st, 2009, in Vienna, Austria, to discuss the latest advances at the forefront of basic and clinical nuclear receptor research and its potential implications for liver diseases. This article reports the highlights of the conference and summarizes the main conclusions emphasizing the relevance for clinical and experimental hepatology. The confluence of nuclear receptors as central transcriptional regulators, acting as sensors and adaptors to many of the small molecules present in the intracellular milieu of all the cells of the liver, provides a current framework to address a broader physiological understanding of the liver. The next stage will be the design and testing of safe and effective therapeutics.


Baghdasaryan A.,Medical University of Graz | Claudel T.,Medical University of Graz | Kosters A.,Texas Childrens Liver Center | Gumhold J.,Medical University of Graz | And 7 more authors.
Gut | Year: 2010

Background and aim: Chronic cholangiopathies have limited therapeutic options and represent an important indication for liver transplantation. Curcumin, the yellow pigment of the spice turmeric, has pleiotropic actions and attenuates hepatic damage in animal models of chemically-induced liver injury. Whether curcumin has beneficial effects in cholangiopathies is unknown. Methods: Potential anticholestatic, anti-inflammatory and antifibrotic mechanisms of curcumin were explored in vivo in Mdr2-/- mice as a murine model of chronic cholangiopathy; as well as in vitro in a cholangiocyte cell line (HuCCT1) and portal myofibroblasts (MFBs) isolated from Mdr2-/- mice. Results: Liver damage, cholestasis and fibrosis were reduced in Mdr2 -/- mice after curcumin feeding. Moreover, curcumin inhibited cholangiocyte proliferation and expression of activation marker vascular cell adhesion molecule-1 in Mdr2-/- mice. Curcumin - similar to PPARγ synthetic agonist troglitazone - directly inhibited TNF-α-induced inflammatory activation of cholangiocytes in vitro, whereas these beneficial effects of curcumin were largely blocked by a PPARγ synthetic antagonist. In addition, curcumin blocked proliferation and activation of portal MFBs by inhibiting ERK1/2 phosphorylation, thus contributing to reduced fibrogenesis. Conclusions: These results show that curcumin may have multiple targets in liver including activation of PPARγ in cholangiocytes and inhibition of ERK1/2 signalling in MFBs, thereby modulating several central cellular events in a mouse model of cholangiopathy. Targeting these pathways may be a promising therapeutic approach to cholangiopathies.


Tackett B.C.,Texas Childrens Liver Center | Tackett B.C.,Baylor College of Medicine | Sun H.,Texas Childrens Liver Center | Mei Y.,Texas Childrens Liver Center | And 10 more authors.
American Journal of Physiology - Gastrointestinal and Liver Physiology | Year: 2014

Extracellular nucleotides via activation of P2 purinergic receptors influence hepatocyte proliferation and liver regeneration in response to 70% partial hepatectomy (PH). Adult hepatocytes express multiple P2Y (G protein-coupled) and P2X (ligand-gated ion channels) purinergic receptor subtypes. However, the identity of key receptor subtype(s) important for efficient hepatocyte proliferation in regenerating livers remains unknown. To evaluate the impact of P2Y2 purinergic receptor-mediated signaling on hepatocyte proliferation in regenerating livers, wild-type (WT) and P2Y2 purinergic receptor knockout (P2Y2—/—) mice were subjected to 70% PH. Liver tissues were analyzed for activation of early events critical for hepatocyte priming and subsequent cell cycle progression. Our findings suggest that early activation of p42/44 ERK MAPK (5 min), early growth response-1 (Egr-1) and activator protein-1 (AP-1) DNA-binding activity (30 min), and subsequent hepatocyte proliferation (24-72 h) in response to 70% PH were impaired in P2Y2—/— mice. Interestingly, early induction of cytokines (TNF-a, IL-6) and cytokine-mediated signaling (NF-kB, STAT-3) were intact in P2Y2—/— remnant livers, uncovering the importance of cytokine-independent and nucleotide-dependent early priming events critical for subsequent hepatocyte proliferation in regenerating livers. Hepatocytes isolated from the WT and P2Y2—/— mice were treated with ATP or ATP7S for 5-120 min and 12-24 h. Extracellular ATP alone, via activation of P2Y2 purinergic receptors, was sufficient to induce ERK phosphorylation, Egr-1 protein expression, and key cyclins and cell cycle progression of hepatocytes in vitro. Collectively, these findings highlight the functional significance of P2Y2 purinergic receptor activation for efficient hepatocyte priming and proliferation in response to PH. © 2014 the American Physiological Society.


PubMed | Texas Childrens Liver Center, University of Houston and Baylor College of Medicine
Type: Journal Article | Journal: American journal of physiology. Gastrointestinal and liver physiology | Year: 2014

Extracellular nucleotides via activation of P2 purinergic receptors influence hepatocyte proliferation and liver regeneration in response to 70% partial hepatectomy (PH). Adult hepatocytes express multiple P2Y (G protein-coupled) and P2X (ligand-gated ion channels) purinergic receptor subtypes. However, the identity of key receptor subtype(s) important for efficient hepatocyte proliferation in regenerating livers remains unknown. To evaluate the impact of P2Y2 purinergic receptor-mediated signaling on hepatocyte proliferation in regenerating livers, wild-type (WT) and P2Y2 purinergic receptor knockout (P2Y2-/-) mice were subjected to 70% PH. Liver tissues were analyzed for activation of early events critical for hepatocyte priming and subsequent cell cycle progression. Our findings suggest that early activation of p42/44 ERK MAPK (5 min), early growth response-1 (Egr-1) and activator protein-1 (AP-1) DNA-binding activity (30 min), and subsequent hepatocyte proliferation (24-72 h) in response to 70% PH were impaired in P2Y2-/- mice. Interestingly, early induction of cytokines (TNF-, IL-6) and cytokine-mediated signaling (NF-B, STAT-3) were intact in P2Y2-/- remnant livers, uncovering the importance of cytokine-independent and nucleotide-dependent early priming events critical for subsequent hepatocyte proliferation in regenerating livers. Hepatocytes isolated from the WT and P2Y2-/- mice were treated with ATP or ATPS for 5-120 min and 12-24 h. Extracellular ATP alone, via activation of P2Y2 purinergic receptors, was sufficient to induce ERK phosphorylation, Egr-1 protein expression, and key cyclins and cell cycle progression of hepatocytes in vitro. Collectively, these findings highlight the functional significance of P2Y2 purinergic receptor activation for efficient hepatocyte priming and proliferation in response to PH.


Leung D.H.,Baylor College of Medicine | Leung D.H.,Texas Childrens Liver Center | Khan M.,Texas Childrens Liver Center | Minard C.G.,Baylor College of Medicine | And 11 more authors.
Hepatology | Year: 2015

Up to 10% of cystic fibrosis (CF) children develop cirrhosis by the first decade. We evaluated the utility of two simple biomarkers, aspartate aminotransferase to platelet ratio index (APRI) and FIB-4, in predicting degree of fibrosis in pediatric CF liver disease (CFLD) validated by liver biopsy. In this retrospective, cross-sectional study, 67 children with CFLD had dual-pass liver biopsies and 104 age- and sex-matched CF children without liver disease (CFnoLD) had serum to calculate APRI and FIB-4 collected at enrollment. CFLD was defined as having two of the following: (1) hepatomegaly ± splenomegaly; (2) >6 months elevation of ALT (>1.5× upper limit of normal ULN); or (3) abnormal liver ultrasound findings. Biopsies were staged according to Metavir classification by two blinded pathologists. Receiver operating characteristic (ROC) analysis and continuation ratio logistic regression were performed to assess the predictability of these biomarkers to distinguish CFLD from CFnoLD and determine fibrosis stage-specific cut-off values. The AUC for APRI was better than FIB-4 (0.75 vs. 0.60; P = 0.005) for predicting CFLD and severe CFLD (F3-F4) (0.81). An APRI score >0.264 demonstrated a sensitivity (95% confidence interval [CI]) of 73.1% (60.9, 83.2) and specificity of 70.2% (60.4, 78.8) in predicting CFLD. A 50% increase in APRI was associated with a 2.4-fold (95% CI: 1.7, 3.3) increased odds of having CFLD. APRI demonstrated full agreement with histology staging 37% of the time, but was within one stage 73% of the time. Only FIB-4 predicted portal hypertension at diagnosis (area under the receiver operator characteristic curve [AUC] = 0.91; P < 0.001). Conclusion: This is the first liver biopsy-validated study of APRI and FIB-4 in pediatric CFLD. APRI appears superior to FIB-4 in differentiating CFLD versus CFnoLD. APRI also exhibited a high AUC in predicting severe liver fibrosis with specific cutoffs for lower stages. (Hepatology 2015;62:1576-1583) © 2015 by the American Association for the Study of Liver Diseases.


Maynard J.P.,Texas Childrens Liver Center | Maynard J.P.,Baylor College of Medicine | Lee J.-S.,University of Texas M. D. Anderson Cancer Center | Sohn B.H.,University of Texas M. D. Anderson Cancer Center | And 6 more authors.
Oncotarget | Year: 2015

P2 purinergic receptors are overexpressed in certain cancer tissues, but the pathophysiologic relevance of purinergic signaling in hepatocellular carcinoma (HCC) remains unknown. To examine the role of P2 purinergic signaling in the pathogenesis of HCC and characterize extracellular nucleotide effects on HCC cell proliferation, two independent HCC patient cohorts were analyzed for P2 purinergic receptor expression, and nucleotide treated HCC cell lines were evaluated for effects on proliferation and cell cycle progression. Our studies suggest that multiple P2 purinergic receptor isoforms are overexpressed in liver tumors, as compared to uninvolved liver, and dysregulation of P2 purinergic receptor expression is apparent in HCC cell lines, as compared to human primary hepatocytes. High P2X3 purinergic receptor expression is associated with poor recurrence-free survival (RFS), while high P2Y13 expression is associated with improved RFS. Extracellular nucleotide treatment alone is sufficient to induce cell cycle progression, via activation of JNK signaling, and extracellular ATPmediated activation of P2X3 receptors promotes proliferation in HCC cells. Conclusion: Our analysis of HCC patient livers and HCC cells in vitro identifies a novel role for dysregulation of P2 purinergic signaling in the induction of hyper-proliferative HCC phenotype and identifies P2X3 purinergic receptors as potential new targets for therapy.


PubMed | QIMR Berghofer Medical Research Institute, Texas Childrens Liver Center, University of Queensland and Baylor College of Medicine
Type: Journal Article | Journal: Hepatology (Baltimore, Md.) | Year: 2015

Up to 10% of cystic fibrosis (CF) children develop cirrhosis by the first decade. We evaluated the utility of two simple biomarkers, aspartate aminotransferase to platelet ratio index (APRI) and FIB-4, in predicting degree of fibrosis in pediatric CF liver disease (CFLD) validated by liver biopsy. In this retrospective, cross-sectional study, 67 children with CFLD had dual-pass liver biopsies and 104 age- and sex-matched CF children without liver disease (CFnoLD) had serum to calculate APRI and FIB-4 collected at enrollment. CFLD was defined as having two of the following: (1) hepatomegalysplenomegaly; (2)>6 months elevation of ALT (>1.5 upper limit of normal ULN); or (3) abnormal liver ultrasound findings. Biopsies were staged according to Metavir classification by two blinded pathologists. Receiver operating characteristic (ROC) analysis and continuation ratio logistic regression were performed to assess the predictability of these biomarkers to distinguish CFLD from CFnoLD and determine fibrosis stage-specific cut-off values. The AUC for APRI was better than FIB-4 (0.75 vs. 0.60; P=0.005) for predicting CFLD and severe CFLD (F3-F4) (0.81). An APRI score>0.264 demonstrated a sensitivity (95% confidence interval [CI]) of 73.1% (60.9, 83.2) and specificity of 70.2% (60.4, 78.8) in predicting CFLD. A 50% increase in APRI was associated with a 2.4-fold (95% CI: 1.7, 3.3) increased odds of having CFLD. APRI demonstrated full agreement with histology staging 37% of the time, but was within one stage 73% of the time. Only FIB-4 predicted portal hypertension at diagnosis (area under the receiver operator characteristic curve [AUC 0.91; P<0.001).This is the first liver biopsy-validated study of APRI and FIB-4 in pediatric CFLD. APRI appears superior to FIB-4 in differentiating CFLD versus CFnoLD. APRI also exhibited a high AUC in predicting severe liver fibrosis with specific cutoffs for lower stages.


PubMed | Texas Childrens Liver Center, University of Texas M. D. Anderson Cancer Center and Baylor College of Medicine
Type: Journal Article | Journal: Oncotarget | Year: 2015

P2 purinergic receptors are overexpressed in certain cancer tissues, but the pathophysiologic relevance of purinergic signaling in hepatocellular carcinoma (HCC) remains unknown. To examine the role of P2 purinergic signaling in the pathogenesis of HCC and characterize extracellular nucleotide effects on HCC cell proliferation, two independent HCC patient cohorts were analyzed for P2 purinergic receptor expression, and nucleotide treated HCC cell lines were evaluated for effects on proliferation and cell cycle progression. Our studies suggest that multiple P2 purinergic receptor isoforms are overexpressed in liver tumors, as compared to uninvolved liver, and dysregulation of P2 purinergic receptor expression is apparent in HCC cell lines, as compared to human primary hepatocytes. High P2X3 purinergic receptor expression is associated with poor recurrence-free survival (RFS), while high P2Y13 expression is associated with improved RFS. Extracellular nucleotide treatment alone is sufficient to induce cell cycle progression, via activation of JNK signaling, and extracellular ATP-mediated activation of P2X3 receptors promotes proliferation in HCC cells.Our analysis of HCC patient livers and HCC cells in vitro identifies a novel role for dysregulation of P2 purinergic signaling in the induction of hyper-proliferative HCC phenotype and identifies P2X3 purinergic receptors as potential new targets for therapy.

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