Estrogens stimulate proliferation of intrahepatic biliary epithelium in rats

Alvaro, Domenico; Alpini, Gianfranco; Onori, Paolo; Perego, Lucia; Baroni, G. Svegliati; Franchitto, Antonio; Baiocchi, Leonardo; Glaser, Shannon; Sage, Gene Le; Folli, Franco; Gaudio, Eugenio

doi:10.1053/gast.2000.20184

Cited by 165 publications

(186 citation statements)

References 27 publications

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“…4,5,34,35 Estrogens enhance cholangiocyte proliferation in rats. 36 This study provides evidence for how BA differentially regulate cholangiocyte proliferation in small and large ducts. We propose that the activation of proliferative activity in small cholangiocytes in BA-fed rats is likely a result of the de novo expression of ABAT in small cholangiocytes.…”

Section: Discussionmentioning

confidence: 67%

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

2001

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Section: Discussionmentioning

confidence: 67%

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

2001

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“…Both in vitro studies performed in Mz-Cha-1 cells 20 and in vivo data from PBC patients 41 or from the BDL animal model 18,19 suggest that estrogens play a pivotal role in cholangiocyte proliferation. In addition, during cholestasis, estrogen serum levels are increased.…”

Section: Discussionmentioning

confidence: 99%

Ezrin-Radixin-Moesin-Binding Phosphoprotein (EBP50), an Estrogen-Inducible Scaffold Protein, Contributes to Biliary Epithelial Cell Proliferation

Fouassier

Rosenberg

Mergey

et al. 2009

The American Journal of Pathology

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Ezrin-radixin-moesin-binding phosphoprotein 50 (EBP50) anchors and regulates apical membrane proteins in epithelia. EBP50 is inducible by estrogen and may affect cell proliferation, although this latter function remains unclear. The goal of this study was to determine whether EBP50 was implicated in the ductular reaction that occurs in liver disease. EBP50 expression was examined in normal human liver, in human cholangiopathies (ie, cystic fibrosis, primary biliary cirrhosis, and primary sclerosing cholangitis), and in rats subjected to bile-duct ligation. The regulation of EBP50 by estrogens and its impact on proliferation were assessed in both bile duct-ligated rats and Mz-Cha-1 human biliary epithelial cells. Analyses of cell isolates and immunohistochemical studies showed that in normal human liver, EBP50 is expressed in the canalicular membranes of hepatocytes and, together with ezrin and cystic fibrosis transmembrane conductance regulator, in the apical domains of cholangiocytes. In both human cholangiopathies and bile duct-ligated rats, EBP50 was redistributed to the cytoplasmic and nuclear compartments. EBP50 underwent a transient increase in rat cholangiocytes after bile-duct ligation, whereas such expression was down-regulated in ovariectomized rats. In addition, in Mz-Cha-1 cells, EBP50 underwent upregulation and intracellular redistribution in response to 17␤-estradiol, whereas its proliferation was inhibited by siRNA-mediated EBP50 knockdown. These results indicate that both the expression and distribution of EBP50 are regulated by estrogens and contribute to the proliferative response in biliary epithelial cells. (Am J

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“…[5][6][7][8] Previous experimental and clinical studies have shown that proliferating cholangiocytes show an enhanced response to hormones, neuropeptides, growth factors, and cytokines and secrete large amounts of different agents, 9,10,13-18,42-44 which through autocrine mechanisms sustain the cell proliferative machinery and exert anti-apoptotic effects. Among these agents, estrogens and IGF1 10,[13][14][15][16][17][18][42][43][44] play a crucial role in sustaining proliferation of rat and human cholangiocytes by acting on specific receptors. They exert additive proliferative effects at both receptor and postreceptor levels in which survival pathways are activated.…”

Section: Estrogens Igf1 and Adpkd 329mentioning

confidence: 99%

“…Furthermore, recent evidence indicates that the intrahepatic biliary epithelium is the target of GH/insulin-like growth factor 1 (IGF1) axis 13 and is particularly sensitive to the proliferative effects of IGF1 13 and estrogens. 14 Estrogens exert their proliferative effects either directly or by synergizing growth factors including nerve growth factor and IGF1. [13][14][15][16][17][18] In addition, estrogens induce the expression and secretion of growth factors (IGF1, vascular endothelial growth factor) by epithelial cells.…”

mentioning

confidence: 99%

“…14 Estrogens exert their proliferative effects either directly or by synergizing growth factors including nerve growth factor and IGF1. [13][14][15][16][17][18] In addition, estrogens induce the expression and secretion of growth factors (IGF1, vascular endothelial growth factor) by epithelial cells. 13,19 A number of clinical observations suggest that estrogens play a role in development and progression of hepatic cysts in ADPKDf.…”

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confidence: 99%

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Morphological and Functional Features of Hepatic Cyst Epithelium in Autosomal Dominant Polycystic Kidney Disease

Alvaro

Onori

Alpini

et al. 2008

The American Journal of Pathology

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We evaluated the morphological and functional features of hepatic cyst epithelium in adult autosomal dominant polycystic kidney disease (ADPKD). In six ADPKD patients, we investigated the morphology of cyst epithelium apical surface by scanning electron microscopy and the expression of estrogen receptors (ERs), insulin-like growth factor 1 (IGF1), IGF1 receptors (IGF1-R), growth hormone receptor, the proliferation marker proliferating cell nuclear antigen, and pAKT by immunohistochemistry and immunofluorescence. Proliferation of liver cyst-derived epithelial cells was evaluated by both MTS proliferation assay and [ 3 H]thymidine incorporation into DNA. The hepatic cyst epithelium displayed heterogeneous features, being normal in small cysts (<1 cm), characterized by rare or shortened cilia in 1-to 3-cm cysts, and exhibiting the absence of both primary cilia and microvilli in large cysts (>3 cm). Cyst epithelium showed marked immunohistochemical expression of ER, growth hormone receptor, IGF1, IGF1-R, proliferating cell nuclear antigen, and pAKT. IGF1 was 10-fold more enriched in the hepatic cyst fluid than in serum. Serum-deprived liver cyst-derived epithelial cells proliferated when exposed to 17␤-estradiol and IGF1 and when exposed to human cyst fluid. ER or IGF1-R antagonists inhibited the proliferative effect of serum readmission, cyst fluid, 17␤-estradiol, and IGF1. Our findings could explain the role of estrogens in accelerating the progression of ADPKD and may suggest a potential benefit of therapeutic strategies based on estrogen antagonism.

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Estrogens stimulate proliferation of intrahepatic biliary epithelium in rats

Cited by 165 publications

References 27 publications

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

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

Ezrin-Radixin-Moesin-Binding Phosphoprotein (EBP50), an Estrogen-Inducible Scaffold Protein, Contributes to Biliary Epithelial Cell Proliferation

Morphological and Functional Features of Hepatic Cyst Epithelium in Autosomal Dominant Polycystic Kidney Disease

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