scholarly journals Castration inhibits biliary proliferation induced by bile duct obstruction: novel role for the autocrine trophic effect of testosterone

2011 ◽  
Vol 301 (6) ◽  
pp. G981-G991 ◽  
Author(s):  
Fuquan Yang ◽  
Sally Priester ◽  
Paolo Onori ◽  
Julie Venter ◽  
Anastasia Renzi ◽  
...  
Keyword(s):  
Bile Duct ◽  
Intrahepatic Bile Duct ◽  
Serum Levels ◽  
Bile Secretion ◽  
Male Rats ◽  
Trophic Effect ◽  
Knock Down ◽  
Duct Ligation ◽  
Normal Rat ◽  
Camp Levels

Increased cholangiocyte growth is critical for the maintenance of biliary mass during liver injury by bile duct ligation (BDL). Circulating levels of testosterone decline following castration and during cholestasis. Cholangiocytes secrete sex hormones sustaining cholangiocyte growth by autocrine mechanisms. We tested the hypothesis that testosterone is an autocrine trophic factor stimulating biliary growth. The expression of androgen receptor (AR) was determined in liver sections, male cholangiocytes, and cholangiocyte cultures [normal rat intrahepatic cholangiocyte cultures (NRICC)]. Normal or BDL (immediately after surgery) rats were treated with testosterone or antitestosterone antibody or underwent surgical castration (followed by administration of testosterone) for 1 wk. We evaluated testosterone serum levels; intrahepatic bile duct mass (IBDM) in liver sections of female and male rats following the administration of testosterone; and secretin-stimulated cAMP levels and bile secretion. We evaluated the expression of 17β-hydroxysteroid dehydrogenase 3 (17β-HSD3, the enzyme regulating testosterone synthesis) in cholangiocytes. We evaluated the effect of testosterone on the proliferation of NRICC in the absence/presence of flutamide (AR antagonist) and antitestosterone antibody and the expression of 17β-HSD3. Proliferation of NRICC was evaluated following stable knock down of 17β-HSD3. We found that cholangiocytes and NRICC expressed AR. Testosterone serum levels decreased in castrated rats (prevented by the administration of testosterone) and rats receiving antitestosterone antibody. Castration decreased IBDM and secretin-stimulated cAMP levels and ductal secretion of BDL rats. Testosterone increased 17β-HSD3 expression and proliferation in NRICC that was blocked by flutamide and antitestosterone antibody. Knock down of 17β-HSD3 blocks the proliferation of NRICC. Drug targeting of 17β-HSD3 may be important for managing cholangiopathies.

scholarly journals Melatonin inhibits cholangiocyte hyperplasia in cholestatic rats by interaction with MT1 but not MT2 melatonin receptors

2011 ◽  
Vol 301 (4) ◽  
pp. G634-G643 ◽  
Author(s):  
Anastasia Renzi ◽  
Shannon Glaser ◽  
Sharon DeMorrow ◽  
Romina Mancinelli ◽  
Fanyin Meng ◽  
...  
Keyword(s):  
Bile Duct ◽  
Clock Genes ◽  
Intrahepatic Bile Duct ◽  
Serum Levels ◽  
Melatonin Receptors ◽  
Camp Levels ◽  
Cell Mitosis

In bile duct-ligated (BDL) rats, large cholangiocytes proliferate by activation of cAMP-dependent signaling. Melatonin, which is secreted from pineal gland as well as extrapineal tissues, regulates cell mitosis by interacting with melatonin receptors (MT1 and MT2) modulating cAMP and clock genes. In the liver, melatonin suppresses oxidative damage and ameliorates fibrosis. No information exists regarding the role of melatonin in the regulation of biliary hyperplasia. We evaluated the mechanisms of action by which melatonin regulates the growth of cholangiocytes. In normal and BDL rats, we determined the hepatic distribution of MT1, MT2, and the clock genes, CLOCK, BMAL1, CRY1, and PER1. Normal and BDL (immediately after BDL) rats were treated in vivo with melatonin before evaluating 1) serum levels of melatonin, bilirubin, and transaminases; 2) intrahepatic bile duct mass (IBDM) in liver sections; and 3) the expression of MT1 and MT2, clock genes, and PKA phosphorylation. In vitro, large cholangiocytes were stimulated with melatonin in the absence/presence of luzindole (MT1/MT2 antagonist) and 4-phenyl-2-propionamidotetralin (MT2 antagonist) before evaluating cell proliferation, cAMP levels, and PKA phosphorylation. Cholangiocytes express MT1 and MT2, CLOCK, BMAL1, CRY1, and PER1 that were all upregulated following BDL. Administration of melatonin to BDL rats decreased IBDM, serum bilirubin and transaminases levels, the expression of all clock genes, cAMP levels, and PKA phosphorylation in cholangiocytes. In vitro, melatonin decreased the proliferation, cAMP levels, and PKA phosphorylation, decreases that were blocked by luzindole. Melatonin may be important in the management of biliary hyperplasia in human cholangiopathies.

Upregulation of secretin receptor gene expression in rat cholangiocytes after bile duct ligation

1994 ◽  
Vol 266 (5) ◽  
pp. G922-G928 ◽  
Author(s):  
G. Alpini ◽  
C. D. Ulrich ◽  
J. O. Phillips ◽  
L. D. Pham ◽  
L. J. Miller ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bile Duct ◽  
Bile Duct Ligation ◽  
Intrahepatic Bile Duct ◽  
Liver Cells ◽  
Bile Secretion ◽  
Rnase Protection ◽  
Secretin Receptor ◽  
Duct Ligation ◽  
Sr Gene

Secretion stimulates ductular bile secretion by binding to receptors on intrahepatic bile duct epithelial cells (i.e., cholangiocytes). In the rat, this choleretic effect increases after bile duct ligation (BDL). Although cholangiocyte proliferation induced by BDL contributes to secretin-induced hypercholeresis, the mechanisms modulating these alterations in secretin-induced ductular bile secretion are obscure. Thus we studied the expression of secretin receptor mRNA (SR-mRNA) in purified liver cells from normal and BDL rats. Northern blot analysis and RNase protection assays with mRNA from purified liver cells demonstrated SR-mRNA only in cholangiocytes; moreover, SR gene expression showed a seven- to ninefold increase in individual cholangiocytes from BDL rats compared with controls. This increase in SR-mRNA expression was related to a similar increase in the rate of transcription of SR-mRNA in cholangiocytes from BDL rats. Thus our studies indicate that 1) SR-mRNA is detected in liver only in cholangiocytes; 2) BDL causes an increase in SR-mRNA in individual cholangiocytes; and 3) the increase in SR-mRNA after BDL is partly related to an increase in the rate of transcription of SR-mRNA by cholangiocytes after BDL. Our data suggest that upregulation of the SR gene may contribute to secretin-induced hypercholeresis.

Dopaminergic inhibition of secretin-stimulated choleresis by increased PKC-γ expression and decrease of PKA activity

2003 ◽  
Vol 284 (4) ◽  
pp. G683-G694 ◽  
Author(s):  
Shannon Glaser ◽  
Domenico Alvaro ◽  
Tania Roskams ◽  
Jo Lynne Phinizy ◽  
George Stoica ◽  
...  
Keyword(s):  
Nervous System ◽  
Bile Duct ◽  
Intrahepatic Bile Duct ◽  
Mechanisms Of Action ◽  
Dopaminergic Receptors ◽  
Inhibitory Effects ◽  
Pkc Isoforms ◽  
Camp Levels ◽  
Experimental Cholestasis

To determine the role and mechanisms of action by which dopaminergic innervation modulates ductal secretion in bile duct-ligated rats, we determined the expression of D1, D2, and D3 dopaminergic receptors in cholangiocytes. We evaluated whether D1, D2 (quinelorane), or D3 dopaminergic receptor agonists influence basal and secretin-stimulated choleresis and lumen expansion in intrahepatic bile duct units (IBDU) and cAMP levels in cholangiocytes in the absence or presence of BAPTA-AM, chelerythrine, 1-(5-isoquinolinylsulfonyl)-2-methyl piperazine (H7), or rottlerin. We evaluated whether 1) quinelorane effects on ductal secretion were associated with increased expression of Ca2+-dependent PKC isoforms and 2) increased expression of PKC causes inhibition of PKA activity. Quinelorane inhibited secretin-stimulated choleresis in vivo and IBDU lumen space, cAMP levels, and PKA activity in cholangiocytes. The inhibitory effects of quinelorane on secretin-stimulated ductal secretion and PKA activity were blocked by BAPTA-AM, chelerythrine, and H7. Quinelorane effects on ductal secretion were associated with activation of the Ca2+-dependent PKC-γ but not other PKC isoforms. The dopaminergic nervous system counterregulates secretin-stimulated ductal secretion in experimental cholestasis.

scholarly journals Investigating the neuroprotective effects of Resveratrol on encephalopathy induced by bile duct ligation in male rats

2020 ◽  
Vol 10 (3) ◽  
pp. 5512-5515
Keyword(s):  
Bile Duct ◽  
Bile Duct Ligation ◽  
Male Rats ◽  
Definitive Treatment ◽  
Neuroprotective Effects ◽  
Beneficial Effects ◽  
Duct Ligation ◽  
Ischemic Diseases ◽  
Anti Inflammatory ◽  
First Time

Hepatic encephalopathy (HE) is a complex neuropsychiatric disorder without definitive treatment. The precise mechanism that leads to HE is not fully understood. Resveratrol (RES) is a polyphenol compound with antioxidant and anti-inflammatory properties that mitigates the progression of different illnesses such as inflammatory and ischemic diseases. This study reports the effects of RES on neuronal injures in bile duct-ligated rats. The rats were randomly distributed into three groups including sham, bile duct ligation (BDL), and BDL + RES. Behavioral and biochemical studies were performed to evaluate neuronal injuries. The obtained data indicate that BDL experienced a balanced impairment and an increase in the hepatic enzymes. RES had a preserving role in the treated animals. Moreover, RES treatment declined neuronal injuries induced by BDL. For the first time, the results of this study showed that RES has beneficial effects in the rat model of HE probably because of its antioxidant and anti-inflammatory properties.

scholarly journals OBSERVATIONS CONCERNING THE PRODUCTION AND EXCRETION OF CHOLESTEROL IN MAMMALS

1953 ◽  
Vol 97 (4) ◽  
pp. 511-524 ◽  
Author(s):  
Sanford O. Byers ◽  
Meyer Friedman ◽  
Max W. Biggs ◽  
Barbara Gunning
Keyword(s):  
Bile Duct ◽  
Plasma Proteins ◽  
Bile Duct Ligation ◽  
Sodium Cholate ◽  
Normal Rate ◽  
Duct Ligation ◽  
Normal Rat ◽  
Binding Power ◽  
Intravenous Sodium ◽  
Cholesterol Binding

Accumulation of cholate in plasma is the immediate cause of hypercholesteremia in the rat with bile duct ligation and in the normal rat given intravenous sodium cholate. The hypercholesteremia induced by cholate administration does not appear to be dependent upon any preceding change in the rates of absorption, excretion, synthesis, or redistribution of cholesterol in the tissues of the animal. Cholate administration seems to induce hypercholesteremia by impeding the normal rate of passage of cholesterol from the plasma into the liver; this impedance is probably due to an alteration of the cholesterol-binding power of plasma proteins induced by cholate. The chemical and physiological implications of this finding are discussed.

Polarized expression and function of P2Y ATP receptors in rat bile duct epithelia

2001 ◽  
Vol 281 (4) ◽  
pp. G1059-G1067 ◽  
Author(s):  
Jonathan A. Dranoff ◽  
Anatoly I. Masyuk ◽  
Emma A. Kruglov ◽  
Nicholas F. LaRusso ◽  
Michael H. Nathanson
Keyword(s):  
Bile Duct ◽  
Intrahepatic Bile Duct ◽  
P2y Receptors ◽  
Bile Secretion ◽  
Extracellular Nucleotides ◽  
Apical Plasma Membrane ◽  
Receptor Subtypes ◽  
P2y Receptor ◽  
Atp Receptors ◽  
And Function

Extracellular nucleotides may be important regulators of bile ductular secretion, because cholangiocytes express P2Y ATP receptors and nucleotides are found in bile. However, the expression, distribution, and function of specific P2Y receptor subtypes in cholangiocytes are unknown. Thus our aim was to determine the subtypes, distribution, and role in secretion of P2Y receptors expressed by cholangiocytes. The molecular subtypes of P2Y receptors were determined by RT-PCR. Functional studies measuring cytosolic Ca2+ (Ca[Formula: see text]) signals and bile ductular pH were performed in isolated, microperfused intrahepatic bile duct units (IBDUs). PCR products corresponding to P2Y1, P2Y2, P2Y4, P2Y6, and P2X4 receptor subtypes were identified. Luminal perfusion of ATP into IBDUs induced increases in Ca[Formula: see text] that were inhibited by apyrase and suramin. Luminal ATP, ADP, 2-methylthioadenosine 5′-triphosphate, UTP, and UDP each increased Ca[Formula: see text]. Basolateral addition of adenosine 5′- O-(3-thiotriphosphate) (ATP-γ-S), but not ATP, to the perifusing bath increased Ca[Formula: see text]. IBDU perfusion with ATP-γ-S induced net bile ductular alkalization. Cholangiocytes express multiple P2Y receptor subtypes that are expressed at the apical plasma membrane domain. P2Y receptors are also expressed on the basolateral domain, but their activation is attenuated by nucleotide hydrolysis. Activation of ductular P2Y receptors induces net ductular alkalization, suggesting that nucleotide signaling may be an important regulator of bile secretion by the liver.

Knockout of histidine decarboxylase decreases bile duct ligation-induced biliary hyperplasia via downregulation of the histidine decarboxylase/VEGF axis through PKA-ERK1/2 signaling

2014 ◽  
Vol 307 (8) ◽  
pp. G813-G823 ◽  
Author(s):  
Allyson Graf ◽  
Fanyin Meng ◽  
Laura Hargrove ◽  
Lindsey Kennedy ◽  
Yuyan Han ◽  
...  
Keyword(s):  
Bile Duct ◽  
Protein Expression ◽  
Histidine Decarboxylase ◽  
Intrahepatic Bile Duct ◽  
Cytokeratin 19 ◽  
Wild Type ◽  
Histamine Secretion ◽  
Duct Ligation ◽  
Hematoxylin And Eosin

Histidine is converted to histamine by histidine decarboxylase (HDC). We have shown that cholangiocytes 1) express HDC, 2) secrete histamine, and 3) proliferate after histamine treatment via ERK1/2 signaling. In bile duct-ligated (BDL) rodents, there is enhanced biliary hyperplasia, HDC expression, and histamine secretion. This studied aimed to demonstrate that knockdown of HDC inhibits biliary proliferation via downregulation of PKA/ERK1/2 signaling. HDC−/− mice and matching wild-type (WT) were subjected to sham or BDL. After 1 wk, serum, liver blocks, and cholangiocytes were collected. Immunohistochemistry was performed for 1) hematoxylin and eosin, 2) intrahepatic bile duct mass (IBDM) by cytokeratin-19, and 3) HDC biliary expression. We measured serum and cholangiocyte histamine levels by enzyme immunoassay. In total liver or cholangiocytes, we studied: 1) HDC and VEGF/HIF-1α expression and 2) PCNA and PKA/ERK1/2 protein expression. In vitro, cholangiocytes were stably transfected with shRNA-HDC plasmids (or control). After transfection we evaluated pPKA, pERK1/2, and cholangiocyte proliferation by immunoblots and MTT assay. In BDL HDC−/− mice, there was decreased IBDM, PCNA, VEGF, and HDC expression compared with BDL WT mice. Histamine levels were decreased in BDL HDC−/−. BDL HDC−/− livers were void of necrosis and inflammation compared with BDL WT. PKA/ERK1/2 protein expression (increased in WT BDL) was lower in BDL HDC−/− cholangiocytes. In vitro, knockdown of HDC decreased proliferation and protein expression of PKA/ERK1/2 compared with control. In conclusion, loss of HDC decreases BDL-induced biliary mass and VEGF/HIF-1α expression via PKA/ERK1/2 signaling. Our data suggest that HDC is a key regulator of biliary proliferation.

scholarly journals LEVELS OF NITRIC OXIDE METABOLITES IN RATS WITH HEPATOPULMONARY SYNDROME

2016 ◽  
Author(s):  
I. Ya. Krynytska
Keyword(s):  
Nitric Oxide ◽  
Bile Duct ◽  
Bronchoalveolar Lavage ◽  
Blood Serum ◽  
Hepatopulmonary Syndrome ◽  
Total Content ◽  
Male Rats ◽  
Duct Ligation ◽  
Nitric Oxide Metabolites ◽  
Experimental Group

<p>Background. System of nitric oxide (NO), which consists of NO, and its metabolites, is very important for<br />various biological processes. NO is signalling molecules and mediators of intracellular and intercellular interaction<br />that causes relaxation of smooth muscles of blood vessel walls, inhibits platelet aggregation and their adherence,<br />is involved in the transmission of nerve impulses, cell proliferation.<br />Objective. The aim of our research was to study the content of nitric oxide metabolites in blood serum and<br />bronchoalveolar lavage, to substantiate their role in pathogenesis of hepatopulmonary syndrome in<br />experiment.<br />Methods. The experiments were performed on 56 outbread male rats, 180-220 g in weight. The first experimental<br />model of hepatopulmonary syndrome (HPS) was made by imposition of double ligature on common<br />bile duct and its further dissection with a scalpel. The second experimental HPS model was made by 8-week intragastric<br />administration of oil solution CCl4 (400 g per 1 L), 0.5 ml per 100 g of body weight on the first day of<br />the experiment, 0.3 ml per 100 g on the third day of the experiment and then every third day until the end of the<br />experiment 0.3 ml per 100 g. A mixture of corn flour, lard and cholesterol and alcohol solution was added to the<br />standard diet of the rats.<br />Results. The total content of nitric oxide metabolites in blood serum of the rats of the experimental group<br />No.1 (on the 31st day after the common bile duct ligation) was significantly increased in 3.9 times (p1&lt;0,001) if<br />compared with the control group №1. In the rats of the 2nd experimental group (with carbon tetrachloride induced<br />cirrhosis) the total content of nitric oxide metabolites in blood serum also significantly increased in 3.1 times<br />(p1&lt;0,001). Comparison of nitric oxide metabolites content in blood serum and bronchoalveolar lavage, which<br />directly indicated about the processes in lung tissue, was great importance.<br />Conclusions. So, in rats with experimental hepatopulmonary syndrome activation of nitroxydergic process<br />by significant increase in nitric oxide metabolites in blood serum and bronchoalveolar lavage took place.<br />KEYWORDS: hepatopulmonary syndrome, nitric oxide metabolites.</p>

The α2-adrenergic receptor agonist UK 14,304 inhibits secretin-stimulated ductal secretion by downregulation of the cAMP system in bile duct-ligated rats

2007 ◽  
Vol 293 (4) ◽  
pp. C1252-C1262 ◽  
Author(s):  
Heather Francis ◽  
Gene LeSage ◽  
Sharon DeMorrow ◽  
Domenico Alvaro ◽  
Yoshiyuki Ueno ◽  
...  
Keyword(s):  
Bile Duct ◽  
Adrenergic Receptors ◽  
Intrahepatic Bile Duct ◽  
Inhibitory Effect ◽  
Bicarbonate Secretion ◽  
Adrenergic Agonist ◽  
Uk 14,304 ◽  
Camp System ◽  
Camp Levels ◽  
Adrenergic Receptor Agonist

Secretin stimulates ductal secretion by activation of cAMP → PKA → CFTR → Cl−/HCO3− exchanger in cholangiocytes. We evaluated the expression of α2A-, α2B-, and α2C-adrenergic receptors in cholangiocytes and the effects of the selective α2-adrenergic agonist UK 14,304, on basal and secretin-stimulated ductal secretion. In normal rats, we evaluated the effect of UK 14,304 on bile and bicarbonate secretion. In bile duct-ligated (BDL) rats, we evaluated the effect of UK 14,304 on basal and secretin-stimulated 1) bile and bicarbonate secretion; 2) duct secretion in intrahepatic bile duct units (IBDU) in the absence or presence of 5-( N-ethyl- N-isopropyl)amiloride (EIPA), an inhibitor of the Na+/H+ exchanger isoform NHE3; and 3) cAMP levels, PKA activity, Cl− efflux, and Cl−/HCO3− exchanger activity in purified cholangiocytes. α2-Adrenergic receptors were expressed by all cholangiocytes in normal and BDL liver sections. UK 14,304 did not change bile and bicarbonate secretion of normal rats. In BDL rats, UK 14,304 inhibited secretin-stimulated 1) bile and bicarbonate secretion, 2) expansion of IBDU luminal spaces, and 3) cAMP levels, PKA activity, Cl− efflux, and Cl−/HCO3− exchanger activity in cholangiocytes. There was decreased lumen size after removal of secretin in IBDU pretreated with UK 14,304. In IBDU pretreated with EIPA, there was no significant decrease in luminal space after removal of secretin in either the absence or presence of UK 14,304. The inhibitory effect of UK 14,304 on ductal secretion is not mediated by the apical cholangiocyte NHE3. α2-Adrenergic receptors play a role in counterregulating enhanced ductal secretion associated with cholangiocyte proliferation in chronic cholestatic liver diseases.

Sign in / Sign up

Export Citation Format

Share Document