Bile acid feeding increased proliferative activity and apical bile acid transporter expression in both small and large rat cholangiocytes

Alpini, Gianfranco

doi:10.1053/jhep.2001.28884

Cited by 116 publications

(150 citation statements)

References 52 publications

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“…11 The differential cross-talk between [Ca 2ϩ ] i and adenylyl cyclase (which leads to stimulatory or inhibitory effects on secretin-stimulated cAMP levels and ductal secretion) 7,9,11,21,22,42 depends on the type of receptor (M3 acetylcholine, 9 D2 dopaminergic, 11 insulin, 21 or gastrin 7 ) or transporter (apical bile acid transporter 22,42,43 ) that is up-or downregulated. 22,42 Although there is activation of [Ca 2ϩ ] i but not PKC with acetylcholine, 9 there is activation of intracellular IP 3 /Ca 2ϩ and specific PKC isoforms with D2 dopaminergic agonists (PKC-␥), 11 gastrin (PKC-␣), 7 insulin (PKC-␣), 21 or ursodeoxycholate (PKC-␣). 42 These interactions can induce a differential cross-talk between [Ca 2ϩ ] i and specific adenylate cyclase isoforms leading to inhibition or stimulation of adenylate cyclase and secretin-stimulated ductal secretion.…”

Section: Discussionmentioning

confidence: 99%

“…The amount of protein loaded was normalized by immunoblots for ␤-actin. 22 The intensity of the bands was determined via scanning video densitometry using the ChemiImager 4000 low light imaging system (Alpha Innotech Corp., San Leandro, CA). We evaluated (via immunoblotting) the protein expression for ␣-1A/1C, -1B, or ␤-1 adrenergic receptors in basolateral or apical cholangiocyte membranes 23 from BDL rats.…”

Section: Purification Of Cholangiocytes and Ibdusmentioning

confidence: 99%

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α-1 adrenergic receptor agonists modulate ductal secretion of BDL rats via Ca²⁺- and PKC-dependent stimulation of cAMP

et al. 2004

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Acetylcholine potentiates secretin-stimulated ductal secretion by Ca 2؉ -calcineurin-mediated modulation of adenylyl cyclase. D2 dopaminergic receptor agonists inhibit secretin-stimulated ductal secretion via activation of protein kinase C (PKC)-␥. No information exists regarding the effect of adrenergic receptor agonists on ductal secretion in a model of cholestasis induced by bile duct ligation (BDL). We evaluated the expression of ␣-1A/1C, -1␤ and ␤-1 adrenergic receptors in liver sections and cholangiocytes from normal and BDL rats. We evaluated the effects of the ␣-1 and ␤-1 adrenergic receptor agonists (phenylephrine and dobutamine, respectively) on bile and bicarbonate secretion and cholangiocyte IP 3 and Ca 2؉ levels in normal and BDL rats. We measured the effect of phenylephrine on lumen expansion in intrahepatic bile duct units (IBDUs) and cyclic adenosine monophosphate (cAMP) levels in cholangiocytes from BDL rats in the absence or presence of BAPTA/AM and Gö6976 (a PKC-␣ inhibitor). We evaluated if the effects of phenylephrine on ductal secretion were associated with translocation of PKC isoforms leading to increased protein kinase A activity. ␣-1 and ␤-1 adrenergic receptors were present mostly in the basolateral domain of cholangiocytes and, following BDL, their expression increased. Phenylephrine, but not dobutamine, increased secretin-stimulated choleresis in BDL rats. Phenylephrine did not alter basal but increased secretin-stimulated IBDU lumen expansion and cAMP levels, which were blocked by BAPTA/AM and Gö6976. S ecretin stimulates ductal HCO 3Ϫ secretion 1-5 by interacting with receptors expressed only by rat cholangiocytes. 6 This interaction induces an increase in intracellular cyclic adenosine 3Ј,5Ј-monophosphate (cAMP) levels, 4,5,7 which leads to the opening of cystic fibrosis transmembrane conductance regulator channels, 8 followed by activation of the apically located Cl Ϫ /HCO 3 Ϫ exchanger 9 with secretion of HCO 3 Ϫ into bile. 1 Acetylcholine increases intracellular Ca 2ϩ ([Ca 2ϩ ] i ) levels and oscillations in rat cholangiocytes due to influx of extracellular Ca 2ϩ and mobilization of thapsigarginsensitive [Ca 2ϩ ] i stores. 10 It also increases secretin-stimulated ductal HCO 3 Ϫ secretion via Ca 2ϩ -calcineurin mediated modulation of adenylyl cyclase. 9 The D2 dopaminergic receptor agonist quinelorane inhibits secretinstimulated ductal secretion via activation of the Ca 2ϩ -dependent protein kinase C (PKC)-␥. 11 Adrenergic nerve stimulation causes a decrease in bile flow in the isolated perfused rat liver via interaction with ␣-1 adrenergic receptors. 12 In isolated perfused rat liver, adrenaline induces

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Section: Discussionmentioning

confidence: 99%

Section: Purification Of Cholangiocytes and Ibdusmentioning

confidence: 99%

α-1 adrenergic receptor agonists modulate ductal secretion of BDL rats via Ca²⁺- and PKC-dependent stimulation of cAMP

et al. 2004

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“…Blots were normalized against the housekeeping protein, b-actin. 35 The intensity of the bands was determined by scanning video densitometry using the phospho-imager, Storm 860, Amersham Biosciences (Piscataway, NJ, USA) using the ImageQuant TLV 2003.02.…”

Section: Evaluation Of Cholangiocyte Proliferation and Camp Levelsmentioning

confidence: 99%

“…The amount of protein loaded was normalized against b-actin. 35 Proteins (10 mg) were visualized using chemiluminescence (ECL Plus kit, Amersham Life Science). The intensity of the bands was determined by scanning video densitometry using the phospho-imager, Storm 860, Amersham Biosciences using the ImageQuant TLV 2003.02.…”

Section: In Vitro Studiesmentioning

confidence: 99%

H3 histamine receptor agonist inhibits biliary growth of BDL rats by downregulation of the cAMP-dependent PKA/ERK1/2/ELK-1 pathway

Francis

Franchitto

Ueno

et al. 2007

Laboratory Investigation

152

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Histamine regulates many functions by binding to four histamine G-coupled receptor proteins (H1R, H2R, H3R and H4R). As H3R exerts their effects by coupling to Ga i/o proteins reducing adenosine 3 0 , 5 0 -monophosphate (cAMP) levels (a key player in the modulation of cholangiocyte hyperplasia/damage), we evaluated the role of H3R in the regulation of biliary growth. We posed the following questions: (1) Do cholangiocytes express H3R? (2) Does in vivo administration of (R)-(a)-(À)-methylhistamine dihydrobromide (RAMH) (H3R agonist), thioperamide maleate (H3R antagonist) or histamine, in the absence/presence of thioperamide maleate, to bile duct ligated (BDL) rats regulate cholangiocyte proliferation? and (3) Does RAMH inhibit cholangiocyte proliferation by downregulation of cAMP-dependent phosphorylation of protein kinase A (PKA)/extracellular signal-regulated kinase 1/2 (ERK1/2)/ets-like gene-1 (Elk-1)? The expression of H3R was evaluated in liver sections by immunohistochemistry and immunofluorescence, and by real-time PCR in cholangiocyte RNA from normal and BDL rats. BDL rats (immediately after BDL) were treated daily with RAMH, thioperamide maleate or histamine in the absence/presence of thioperamide maleate for 1 week. Following in vivo treatment of BDL rats with RAMH for 1 week, and in vitro stimulation of BDL cholangiocytes with RAMH, we evaluated cholangiocyte proliferation, cAMP levels and PKA, ERK1/2 and Elk-1 phosphorylation. Cholangiocytes from normal and BDL rats express H3R. The expression of H3R mRNA increased in BDL compared to normal cholangiocytes. Histamine decreased cholangiocyte growth of BDL rats to a lower extent than that observed in BDL RAMH-treated rats; histamine-induced inhibition of cholangiocyte growth was partly blocked by thioperamide maleate. In BDL rats treated with thioperamide maleate, cholangiocyte hyperplasia was slightly higher than that of BDL rats. In vitro, RAMH inhibited the proliferation of BDL cholangiocytes. RAMH inhibition of cholangiocyte growth was associated with decreased cAMP levels and PKA/ERK1/2/Elk-1 phosphorylation. Downregulation of cAMP-dependent PKA/ERK1/2/Elk-1 phosphorylation (by activation of H3R) is important in the inhibition of cholangiocyte growth in liver diseases.

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“…In a BDL rat model, wherein the number of cholangiocytes dramatically increases as a result of ductular proliferation, taurocholic and taurolithocholic acid interact with cholangiocytes, and an associated increase in secretin receptor gene expression, cAMP levels, and Cl − / HCO 3 − exchanger activity is seen; these suggest the role of bile acids in stimulating cholangiocyte ductal secretion (3,6,12,24,181). Tauroursodeoxycholic acid (TUDCA) and taurohyodeoxycholic (THDCA) acid also have choleretic effects; treatment with TUDCA was associated with increased HCO 3 − secretion, and THDCA treatment led to an increase in biliary secretion of phospholipids (23).…”

Section: Bile-associated Regulatory Factorsmentioning

confidence: 99%

Physiology of Cholangiocytes

Masyuk¹,

Masyuk²,

LaRusso³

2012

Physiology of the Gastrointestinal Tract

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Cholangiocytes are epithelial cells that line the intra-and extrahepatic ducts of the biliary tree. The main physiologic function of cholangiocytes is modification of hepatocyte-derived bile, an intricate process regulated by hormones, peptides, nucleotides, neurotransmitters, and other molecules through intracellular signaling pathways and cascades. The mechanisms and regulation of bile modification are reviewed herein.

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Bile acid feeding increased proliferative activity and apical bile acid transporter expression in both small and large rat cholangiocytes

Cited by 116 publications

References 52 publications

α-1 adrenergic receptor agonists modulate ductal secretion of BDL rats via Ca²⁺- and PKC-dependent stimulation of cAMP

α-1 adrenergic receptor agonists modulate ductal secretion of BDL rats via Ca²⁺- and PKC-dependent stimulation of cAMP

H3 histamine receptor agonist inhibits biliary growth of BDL rats by downregulation of the cAMP-dependent PKA/ERK1/2/ELK-1 pathway

Physiology of Cholangiocytes

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Bile acid feeding increased proliferative activity and apical bile acid transporter expression in both small and large rat cholangiocytes

Cited by 116 publications

References 52 publications

α-1 adrenergic receptor agonists modulate ductal secretion of BDL rats via Ca2+- and PKC-dependent stimulation of cAMP

α-1 adrenergic receptor agonists modulate ductal secretion of BDL rats via Ca2+- and PKC-dependent stimulation of cAMP

H3 histamine receptor agonist inhibits biliary growth of BDL rats by downregulation of the cAMP-dependent PKA/ERK1/2/ELK-1 pathway

Physiology of Cholangiocytes

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α-1 adrenergic receptor agonists modulate ductal secretion of BDL rats via Ca²⁺- and PKC-dependent stimulation of cAMP

α-1 adrenergic receptor agonists modulate ductal secretion of BDL rats via Ca²⁺- and PKC-dependent stimulation of cAMP