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Aapkes SE, Bernts LHP, Barten TRM, van den Berg M, Gansevoort RT, Drenth JPH. Estrogens in polycystic liver disease: A target for future therapies? Liver Int 2021; 41:2009-2019. [PMID: 34153174 PMCID: PMC8456902 DOI: 10.1111/liv.14986] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 03/05/2021] [Accepted: 03/17/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Patients suffering from polycystic liver disease (PLD) can develop large liver volumes, leading to physical and psychological complaints, reducing quality of life. There is an unmet need for new therapies in these patients. Estrogen seems to be a promising target for new therapies. In this review, we summarize the available experimental and epidemiological evidence to unravel the role of estrogens and other female hormones in PLD, to answer clinical questions and identify new targets for therapy. METHODS We identified all experimental and epidemiologial studies concerning estrogens or other female hormones and PLD, to answer pre-defined clinial questions. RESULTS Female sex is the most important risk factor for the presence and severity of disease; estrogen supplementation enhances liver growth and after menopause, liver growth decreases. Experimental studies show the presence of the estrogen receptors alfa and beta on cystic cholangiocytes, and increased in vitro growth after administration of estrogen. CONCLUSIONS Based on the available evidence, female PLD patients should be discouraged from taking estrogen-containing contraceptives or hormone replacement therapy. Since liver growth rates decline after menopause, treatment decisions should be based on measured liver growth in postmenopausal women. Finally, blockage of estrogen receptors or estrogen production is a promising target for new therapies.
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Affiliation(s)
- Sophie E. Aapkes
- Department of NephrologyUniversity Medical Center GroningenUniversity Hospital GroningenGroningenthe Netherlands
| | - Lucas H. P. Bernts
- Department of Gastroenterology and HepatologyRadboud University Medical CenterNijmegenthe Netherlands
| | - Thijs R. M. Barten
- Department of Gastroenterology and HepatologyRadboud University Medical CenterNijmegenthe Netherlands
| | - Marjan van den Berg
- Department of GynaecologyUniversity Medical Center GroningenUniversity Hospital GroningenGroningenthe Netherlands
| | - Ron T. Gansevoort
- Department of NephrologyUniversity Medical Center GroningenUniversity Hospital GroningenGroningenthe Netherlands
| | - Joost P. H. Drenth
- Department of Gastroenterology and HepatologyRadboud University Medical CenterNijmegenthe Netherlands
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Dong XH, Dai D, Yang ZD, Yu XO, Li H, Kang H. S100 calcium binding protein A6 and associated long noncoding ribonucleic acids as biomarkers in the diagnosis and staging of primary biliary cholangitis. World J Gastroenterol 2021; 27:1973-1992. [PMID: 34007134 PMCID: PMC8108032 DOI: 10.3748/wjg.v27.i17.1973] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 01/23/2021] [Accepted: 03/10/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Primary biliary cholangitis (PBC) is a chronic and slowly progressing cholestatic disease, which causes damage to the small intrahepatic bile duct by immuno-regulation, and may lead to cholestasis, liver fibrosis, cirrhosis and, eventually, liver failure.
AIM To explore the potential diagnosis and staging value of plasma S100 calcium binding protein A6 (S100A6) messenger ribonucleic acid (mRNA), LINC00312, LINC00472, and LINC01257 in primary biliary cholangitis.
METHODS A total of 145 PBC patients and 110 healthy controls (HCs) were enrolled. Among them, 80 PBC patients and 60 HCs were used as the training set, and 65 PBC patients and 50 HCs were used as the validation set. The relative expression levels of plasma S100A6 mRNA, long noncoding ribonucleic acids LINC00312, LINC00472 and LINC01257 were analyzed using quantitative reverse transcription-polymerase chain reaction. The bile duct ligation (BDL) mouse model was used to simulate PBC. Then double immunofluorescence was conducted to verify the overexpression of S100A6 protein in intrahepatic bile duct cells of BDL mice. Human intrahepatic biliary epithelial cells were treated with glycochenodeoxycholate to simulate the cholestatic environment of intrahepatic biliary epithelial cells in PBC.
RESULTS The expression of S100A6 protein in intrahepatic bile duct cells was up-regulated in the BDL mouse model compared with sham mice. The relative expression levels of plasma S100A6 mRNA, log10 LINC00472 and LINC01257 were up-regulated while LINC00312 was down-regulated in plasma of PBC patients compared with HCs (3.01 ± 1.04 vs 2.09 ± 0.87, P < 0.0001; 2.46 ± 1.03 vs 1.77 ± 0.84, P < 0.0001; 3.49 ± 1.64 vs 2.37 ± 0.96, P < 0.0001; 1.70 ± 0.33 vs 2.07 ± 0.53, P < 0.0001, respectively). The relative expression levels of S100A6 mRNA, LINC00472 and LINC01257 were up-regulated and LINC00312 was down-regulated in human intrahepatic biliary epithelial cells treated with glycochenodeoxycholate compared with control (2.97 ± 0.43 vs 1.09 ± 0.08, P = 0.0018; 2.70 ± 0.26 vs 1.10 ± 0.10, P = 0.0006; 2.23 ± 0.21 vs 1.10 ± 0.10, P = 0.0011; 1.20 ± 0.04 vs 3.03 ± 0.15, P < 0.0001, respectively). The mean expression of S100A6 in the advanced stage (III and IV) of PBC was up-regulated compared to that in HCs and the early stage (II) (3.38 ± 0.71 vs 2.09 ± 0.87, P < 0.0001; 3.38 ± 0.71 vs 2.57 ± 1.21, P = 0.0003, respectively); and in the early stage (II), it was higher than that in HCs (2.57 ± 1.21 vs 2.09 ± 0.87, P = 0.03). The mean expression of LINC00312 in the advanced stage was lower than that in the early stage and HCs (1.39 ± 0.29 vs 1.56 ± 0.33, P = 0.01; 1.39 ± 0.29 vs 2.07 ± 0.53, P < 0.0001, respectively); in addition, the mean expression of LINC00312 in the early stage was lower than that in HCs (1.56 ± 0.33 vs 2.07 ± 0.53, P < 0.0001). The mean expression of log10 LINC00472 in the advanced stage was higher than those in the early stage and HCs (2.99 ± 0.87 vs 1.81 ± 0.83, P < 0.0001; 2.99 ± 0.87 vs 1.77 ± 0.84, P < 0.0001, respectively). The mean expression of LINC01257 in both the early stage and advanced stage were up-regulated compared with HCs (3.88 ± 1.55 vs 2.37 ± 0.96, P < 0.0001; 3.57 ± 1.79 vs 2.37 ± 0.96, P < 0.0001, respectively). The areas under the curves (AUC) for S100A6, LINC00312, log10 LINC00472 and LINC01257 in PBC diagnosis were 0.759, 0.7292, 0.6942 and 0.7158, respectively. Furthermore, the AUC for these four genes in PBC staging were 0.666, 0.661, 0.839 and 0.5549, respectively. The expression levels of S100A6 mRNA, log10 LINC00472, and LINC01257 in plasma of PBC patients were decreased (2.35 ± 1.02 vs 3.06 ± 1.04, P = 0.0018; 1.99 ± 0.83 vs 2.33 ± 0.96, P = 0.036; 2.84 ± 0.92 vs 3.69 ± 1.54, P = 0.0006), and the expression level of LINC00312 was increased (1.95 ± 0.35 vs 1.73 ± 0.32, P = 0.0007) after treatment compared with before treatment using the paired t-test. Relative expression of S100A6 mRNA was positively correlated with log10 LINC00472 (r = 0.683, P < 0.0001); serum level of collagen type IV was positively correlated with the relative expression of log10 LINC00472 (r = 0.482, P < 0.0001); relative expression of S100A6 mRNA was positively correlated with the serum level of collagen type IV (r = 0.732, P < 0.0001). The AUC for the four biomarkers obtained in the validation set were close to the training set.
CONCLUSION These four genes may potentially act as novel biomarkers for the diagnosis of PBC. Moreover, LINC00472 acts as a potential biomarker for staging in PBC.
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Affiliation(s)
- Xi-Hua Dong
- Department of Laboratory Medicine, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Di Dai
- Department of Laboratory Medicine, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Zhi-Dong Yang
- Department of Laboratory Medicine, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Xiao-Ou Yu
- Department of Laboratory Medicine, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Hua Li
- Department of Laboratory Medicine, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Hui Kang
- Department of Laboratory Medicine, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
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Della Torre S. Non-alcoholic Fatty Liver Disease as a Canonical Example of Metabolic Inflammatory-Based Liver Disease Showing a Sex-Specific Prevalence: Relevance of Estrogen Signaling. Front Endocrinol (Lausanne) 2020; 11:572490. [PMID: 33071979 PMCID: PMC7531579 DOI: 10.3389/fendo.2020.572490] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Accepted: 08/20/2020] [Indexed: 12/11/2022] Open
Abstract
There is extensive evidence supporting the interplay between metabolism and immune response, that have evolved in close relationship, sharing regulatory molecules and signaling systems, to support biological functions. Nowadays, the disruption of this interaction in the context of obesity and overnutrition underlies the increasing incidence of many inflammatory-based metabolic diseases, even in a sex-specific fashion. During evolution, the interplay between metabolism and reproduction has reached a degree of complexity particularly high in female mammals, likely to ensure reproduction only under favorable conditions. Several factors may account for differences in the incidence and progression of inflammatory-based metabolic diseases between females and males, thus contributing to age-related disease development and difference in life expectancy between the two sexes. Among these factors, estrogens, acting mainly through Estrogen Receptors (ERs), have been reported to regulate several metabolic pathways and inflammatory processes particularly in the liver, the metabolic organ showing the highest degree of sexual dimorphism. This review aims to investigate on the interaction between metabolism and inflammation in the liver, focusing on the relevance of estrogen signaling in counteracting the development and progression of non-alcoholic fatty liver disease (NAFLD), a canonical example of metabolic inflammatory-based liver disease showing a sex-specific prevalence. Understanding the role of estrogens/ERs in the regulation of hepatic metabolism and inflammation may provide the basis for the development of sex-specific therapeutic strategies for the management of such an inflammatory-based metabolic disease and its cardio-metabolic consequences.
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Affiliation(s)
- Sara Della Torre
- Department of Pharmaceutical Sciences, University of Milan, Milan, Italy
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4
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The influence of TRAIL, adiponectin and sclerostin alterations on bone loss in BDL-induced cirrhotic rats and the effect of opioid system blockade. Life Sci 2019; 233:116706. [DOI: 10.1016/j.lfs.2019.116706] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Revised: 07/24/2019] [Accepted: 07/28/2019] [Indexed: 12/31/2022]
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Meyer SK, Probert PME, Lakey AK, Leitch AC, Blake LI, Jowsey PA, Cooke MP, Blain PG, Wright MC. Environmental Xenoestrogens Super-Activate a Variant Murine ER Beta in Cholangiocytes. Toxicol Sci 2018; 156:54-71. [PMID: 28013213 PMCID: PMC5356623 DOI: 10.1093/toxsci/kfw234] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
High systemic levels of oestrogens are cholestatic and primary biliary cholangitis (PBC)-which is characterized by hepatic ductular inflammation-is thought to be triggered by exposure to xenobiotics such as those around landfill sites. Xenoestrogens may be a component of this chemical trigger. We therefore hypothesized that xenoestrogens are present at higher levels in the proximity of landfill sites. To test this hypothesis, soil samples were collected, extracts prepared and biological oestrogenic activity examined using cell-based reporter gene assays. Extracts from several sample sites around a landfill site contained a chemical(s) which activated the human ERα in a dose-dependent manner. Extracts from 3 separate control sampling sites were absent of any detectable activity. The mouse ERα and 2 variant mouse ERβ cDNAs were cloned and extracts from sample sites around a landfill site also activated these receptors. One variant murine ERβ was constitutively active when expressed in cholangiocytes, was readily inactivated by ICI182780 and activated in a dose-responsive, ICI182780-inhibitable manner by oestrogen. However, when this receptor was activated by extracts from landfill site soils, ICI182780 failed to antagonize activation. ERβ was readily detectable in murine cholangiocytes and exposing mice acutely to a pooled ER activating soil extracts also gave rise to a mild cholestatic injury. These data indicate that the environment around landfill sites may contain higher levels of xenoestrogens; that these chemicals have "super-activating" characteristics with a variant ERβ and therefore these chemicals could be a component of a xenobiotic insult that triggers PBC.
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Affiliation(s)
- Stephanie K Meyer
- Institute Cellular Medicine, Level 4 Leech, Newcastle University, Newcastle Upon Tyne NE24HH, UK
| | - Philip M E Probert
- Institute Cellular Medicine, Level 4 Leech, Newcastle University, Newcastle Upon Tyne NE24HH, UK.,Health Protection Research Unit, Wolfson Building, Newcastle University, Newcastle Upon Tyne NE2 4AA, UK
| | - Anne K Lakey
- Institute Cellular Medicine, Level 4 Leech, Newcastle University, Newcastle Upon Tyne NE24HH, UK
| | - Alastair C Leitch
- Institute Cellular Medicine, Level 4 Leech, Newcastle University, Newcastle Upon Tyne NE24HH, UK
| | - Lynsay I Blake
- Institute for Sustainability, The Key Building, Newcastle University, Newcastle upon Tyne NE4 5TQ, UK
| | - Paul A Jowsey
- Institute Cellular Medicine, Level 4 Leech, Newcastle University, Newcastle Upon Tyne NE24HH, UK
| | - Martin P Cooke
- School of Civil Engineering and Geosciences, Drummond Building, Newcastle University, Newcastle upon Tyne NE1 7RU, UK
| | - Peter G Blain
- Institute Cellular Medicine, Level 4 Leech, Newcastle University, Newcastle Upon Tyne NE24HH, UK.,Health Protection Research Unit, Wolfson Building, Newcastle University, Newcastle Upon Tyne NE2 4AA, UK
| | - Matthew C Wright
- Institute Cellular Medicine, Level 4 Leech, Newcastle University, Newcastle Upon Tyne NE24HH, UK.,Health Protection Research Unit, Wolfson Building, Newcastle University, Newcastle Upon Tyne NE2 4AA, UK
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Hall C, Sato K, Wu N, Zhou T, Kyritsi K, Meng F, Glaser S, Alpini G. Regulators of Cholangiocyte Proliferation. Gene Expr 2017; 17:155-171. [PMID: 27412505 PMCID: PMC5494439 DOI: 10.3727/105221616x692568] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Cholangiocytes, a small population of cells within the normal liver, have been the focus of a significant amount of research over the past two decades because of their involvement in cholangiopathies such as primary sclerosing cholangitis and primary biliary cholangitis. This article summarizes landmark studies in the field of cholangiocyte physiology and aims to provide an updated review of biliary pathogenesis. The historical approach of rodent extrahepatic bile duct ligation and the relatively recent utilization of transgenic mice have led to significant discoveries in cholangiocyte pathophysiology. Cholangiocyte physiology is a complex system based on heterogeneity within the biliary tree and a number of signaling pathways that serve to regulate bile composition. Studies have expanded the list of neuropeptides, neurotransmitters, and hormones that have been shown to be key regulators of proliferation and biliary damage. The peptide histamine and hormones, such as melatonin and angiotensin, angiotensin, as well as numerous sex hormones, have been implicated in cholangiocyte proliferation during cholestasis. Numerous pathways promote cholangiocyte proliferation during cholestasis, and there is growing evidence to suggest that cholangiocyte proliferation may promote hepatic fibrosis. These pathways may represent significant therapeutic potential for a subset of cholestatic liver diseases that currently lack effective therapies.
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Affiliation(s)
- Chad Hall
- *Research, Central Texas Veterans Health Care System, Temple, TX, USA
- †Baylor Scott & White Digestive Disease Research Center, Temple, TX, USA
- ‡Department of Surgery, Baylor Scott & White and Texas A&M Health Science Center, Temple, TX, USA
| | - Keisaku Sato
- §Operational Funds, Baylor Scott & White, Temple, TX, USA
| | - Nan Wu
- §Operational Funds, Baylor Scott & White, Temple, TX, USA
| | - Tianhao Zhou
- §Operational Funds, Baylor Scott & White, Temple, TX, USA
| | | | - Fanyin Meng
- *Research, Central Texas Veterans Health Care System, Temple, TX, USA
- §Operational Funds, Baylor Scott & White, Temple, TX, USA
- ¶Department of Medicine, Baylor Scott & White and Texas A&M Health Science Center, Temple, TX, USA
| | - Shannon Glaser
- *Research, Central Texas Veterans Health Care System, Temple, TX, USA
- §Operational Funds, Baylor Scott & White, Temple, TX, USA
- ¶Department of Medicine, Baylor Scott & White and Texas A&M Health Science Center, Temple, TX, USA
| | - Gianfranco Alpini
- ‡Department of Surgery, Baylor Scott & White and Texas A&M Health Science Center, Temple, TX, USA
- §Operational Funds, Baylor Scott & White, Temple, TX, USA
- ¶Department of Medicine, Baylor Scott & White and Texas A&M Health Science Center, Temple, TX, USA
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Kobayashi H, Yoshida S, Sun YJ, Shirasawa N, Naito A. 17β-Estradiol in the systemic circulation derives mainly from the parietal cells in cholestatic female rats. J Endocrinol Invest 2016; 39:389-400. [PMID: 26256408 DOI: 10.1007/s40618-015-0374-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2015] [Accepted: 07/29/2015] [Indexed: 01/05/2023]
Abstract
PURPOSE Estrogenic symptoms of liver disease patients including biliary tract disorder with high frequency is observed in clinical cases. However, the origin of 17β-estradiol which is abundant enough to cause symptoms remains uncertain. In male rats, it has been reported that the parietal cells which have an abundance of aromatase-synthesized 17β-estradiol, and a part of 17β-estradiol secreted into the portal vein, may flow into the systemic circulation under a pathophysiological condition of the liver including bile duct ligation (BDL). The aim of this study is to reveal the origin of 17β-estradiol increment in female rats and to investigate the effect of BDL on the ovary during the estrus cycle. METHODS Wistar female rats were used, and the common bile duct was ligated twice and transected completely at 7 days before termination. Serum portal venous and arterial 17β-estradiol levels, Cyp19a1 expressions, aromatase protein levels, and estrogen receptor (ER) α levels in the liver were measured during the estrus cycle. RESULTS Both arterial and portal venous 17β-estradiol levels increased 2.9 times at proestrus and maintained constant levels during the cycle. The expression of Cyp19a1 and aromatase protein in the stomach maintained constant levels, and significantly decreased during the estrus cycle in the ovary. Hepatic ERα protein and Esr1 expressions decrease by BDL in all stages. CONCLUSIONS These results suggest that the increment of serum 17β-estradiol levels in obstructive cholestasis induced by BDL is derived from 17β-estradiol secreted from the parietal cells in females as well as males.
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Affiliation(s)
- H Kobayashi
- Department of Anatomy and Structural Science, Faculty of Medicine, Yamagata University, 2-2-2 Iida-nishi, Yamagata, 990-9585, Japan.
| | - S Yoshida
- Department of Anatomy and Structural Science, Faculty of Medicine, Yamagata University, 2-2-2 Iida-nishi, Yamagata, 990-9585, Japan
| | - Y-J Sun
- Department of Anatomy and Structural Science, Faculty of Medicine, Yamagata University, 2-2-2 Iida-nishi, Yamagata, 990-9585, Japan
| | - N Shirasawa
- Department of Rehabilitation, Faculty of Medical Science and Welfare, Tohoku Bunka Gakuen University, Aoba-ku, Sendai, 980-8579, Japan
| | - A Naito
- Department of Anatomy and Structural Science, Faculty of Medicine, Yamagata University, 2-2-2 Iida-nishi, Yamagata, 990-9585, Japan
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Sun Y, Haapanen K, Li B, Zhang W, Van de Water J, Gershwin ME. Women and primary biliary cirrhosis. Clin Rev Allergy Immunol 2016; 48:285-300. [PMID: 25241227 DOI: 10.1007/s12016-014-8449-4] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Primary biliary cirrhosis occurs more frequently in women, and previous studies indicated that the average age of primary biliary cirrhosis (PBC) onset makes pregnancy in PBC patients uncommon. However, more recently, improved diagnostic testing has enabled detection of PBC in younger women, including those of childbearing age. This has led investigators to become increasingly interested in the relationship between the ontogeny of PBC and pregnancy. Published cases indicate that the typical age for pregnant women to be diagnosed with PBC is in the early 30s, and that during gestation, pruritus and jaundice are the most common symptoms. During gestation, susceptible women may experience onset of PBC resulting from the drastic changes in female hormones; this would include not only the mitochondrial damage due to accumulation of bile acids but also changes in the immune response during the different stages of pregnancy that might play an important role in the breakdown of self-tolerance. The mechanisms underlying the potential relationship between PBC and pregnancy warrant further investigation. For women first diagnosed with PBC during gestation, or those for whom first appearance of a flare up occurs during and postpartum, investigation of the immune response throughout gestation could provide new avenues for immunologic therapeutic intervention and the discovery of new treatment strategies for PBC.
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Affiliation(s)
- Ying Sun
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, 451 Health Sciences Drive, Suite 6510, Davis, CA, 95616, USA
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Abstract
Cholangiocytes are the epithelial cells that line the bile ducts. Along the biliary tree, two different kinds of cholangiocytes exist; small and large cholangiocytes. Each type has important differences in their biological role in physiological and pathological conditions. In response to injury, cholangiocytes become reactive and acquire a neuroendocrine-like phenotype with the secretion of a number of peptides. These molecules act in an autocrine/paracrine fashion to modulate cholangiocyte biology and determine the evolution of biliary damage. The failure of such mechanisms is believed to influence the progression of cholangiopathies, a group of diseases that selectively target biliary cells. Therefore, the understanding of mechanisms regulating cholangiocyte response to injury is expected to foster the development of new therapeutic options to treat biliary diseases. In the present review, we will discuss the most recent findings in the mechanisms driving cholangiocyte adaptation to damage, with particular emphasis on molecular pathways that are susceptible of therapeutic intervention. Morphogenic pathways (Hippo, Notch, Hedgehog), which have been recently shown to regulate biliary ontogenesis and response to injury, will also be reviewed. In addition, the results of ongoing clinical trials evaluating new drugs for the treatment of cholangiopathies will be discussed.
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Franchitto A, Onori P, Renzi A, Carpino G, Mancinelli R, Alvaro D, Gaudio E. Recent advances on the mechanisms regulating cholangiocyte proliferation and the significance of the neuroendocrine regulation of cholangiocyte pathophysiology. ANNALS OF TRANSLATIONAL MEDICINE 2014; 1:27. [PMID: 25332971 DOI: 10.3978/j.issn.2305-5839.2012.10.03] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 09/10/2012] [Accepted: 10/15/2012] [Indexed: 12/14/2022]
Abstract
Cholangiocytes are epithelial cells lining the biliary epithelium. Cholangiocytes play several key roles in the modification of ductal bile and are also the target cells in chronic cholestatic liver diseases (i.e., cholangiopathies) such as PSC, PBC, polycystic liver disease (PCLD) and cholangiocarcinoma (CCA). During these pathologies, cholangiocytes (which in normal condition are in a quiescent state) begin to proliferate acquiring phenotypes of neuroendocrine cells, and start secreting different cytokines, growth factors, neuropeptides, and hormones to modulate cholangiocytes proliferation and interaction with the surrounding environment, trying to reestablish the balance between proliferation/loss of cholangiocytes for the maintenance of biliary homeostasis. The purpose of this review is to summarize the recent findings on the mechanisms regulating cholangiocyte proliferation and the significance of the neuroendocrine regulation of cholangiocyte pathophysiology. To clarify the mechanisms of action of these factors we will provide new potential strategies for the management of chronic liver diseases.
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Affiliation(s)
- Antonio Franchitto
- 1 Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, University of Rome "Sapienza", Rome, Italy ; 2 Eleonora Lorillard Spencer-Cenci Foundation, Rome, Italy ; 3 Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy ; 4 Department of Health Science, University of Rome "Foro Italico", Italy ; 5 Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, Sapienza, University of Rome "Sapienza", Rome, Italy
| | - Paolo Onori
- 1 Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, University of Rome "Sapienza", Rome, Italy ; 2 Eleonora Lorillard Spencer-Cenci Foundation, Rome, Italy ; 3 Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy ; 4 Department of Health Science, University of Rome "Foro Italico", Italy ; 5 Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, Sapienza, University of Rome "Sapienza", Rome, Italy
| | - Anastasia Renzi
- 1 Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, University of Rome "Sapienza", Rome, Italy ; 2 Eleonora Lorillard Spencer-Cenci Foundation, Rome, Italy ; 3 Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy ; 4 Department of Health Science, University of Rome "Foro Italico", Italy ; 5 Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, Sapienza, University of Rome "Sapienza", Rome, Italy
| | - Guido Carpino
- 1 Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, University of Rome "Sapienza", Rome, Italy ; 2 Eleonora Lorillard Spencer-Cenci Foundation, Rome, Italy ; 3 Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy ; 4 Department of Health Science, University of Rome "Foro Italico", Italy ; 5 Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, Sapienza, University of Rome "Sapienza", Rome, Italy
| | - Romina Mancinelli
- 1 Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, University of Rome "Sapienza", Rome, Italy ; 2 Eleonora Lorillard Spencer-Cenci Foundation, Rome, Italy ; 3 Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy ; 4 Department of Health Science, University of Rome "Foro Italico", Italy ; 5 Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, Sapienza, University of Rome "Sapienza", Rome, Italy
| | - Domenico Alvaro
- 1 Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, University of Rome "Sapienza", Rome, Italy ; 2 Eleonora Lorillard Spencer-Cenci Foundation, Rome, Italy ; 3 Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy ; 4 Department of Health Science, University of Rome "Foro Italico", Italy ; 5 Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, Sapienza, University of Rome "Sapienza", Rome, Italy
| | - Eugenio Gaudio
- 1 Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, University of Rome "Sapienza", Rome, Italy ; 2 Eleonora Lorillard Spencer-Cenci Foundation, Rome, Italy ; 3 Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy ; 4 Department of Health Science, University of Rome "Foro Italico", Italy ; 5 Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, Sapienza, University of Rome "Sapienza", Rome, Italy
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Abstract
Primary biliary cirrhosis (PBC) is an autoimmune liver disease characterized by selective destruction of intrahepatic cholangiocytes. Mechanisms underlying the development and progression of the disease are still controversial and largely undefined. Evidence suggests that PBC results from an articulated immunologic response against an immunodominant mitochondrial autoantigen, the E2 component of the pyruvate dehydrogenase complex (PDC-E2); characteristics of the disease are also the presence of disease-specific antimitochondrial autoantibodies (AMAs) and autoreactive CD4 and CD8 T cells. Recent evidence suggests that cholangiocytes show specific immunobiological features that are responsible for the selective targeting of those cells by the immune system. The immune reaction in PBC selectively targets small sized, intrahepatic bile ducts; although a specific reason for that has not been defined yet, it has been established that the biliary epithelium displays a unique heterogeneity, for which the physiological and pathophysiological features of small and large cholangiocytes significantly differ. In this review article, the authors provide a critical overview of the current evidence on the role of cholangiocytes in the immune-mediated destruction of the biliary tree that characterizes PBC.
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Affiliation(s)
- Ana Lleo
- Liver Unit and Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano (MI), Italy
| | - Luca Maroni
- Clinic of Gastroenterology and Hepatology, Università Politecnica delle Marche, Ancona, Italy
| | - Shannon Glaser
- Research, Central Texas Veterans Health Care System, S and W and Texas A and M System Health Science Center, College of Medicine, Temple, Texas,Scott & White Digestive Disease Research Center, S and W and Texas A and M System Health Science Center, College of Medicine, Temple, Texas,Department of Medicine, Division Gastroenterology, S and W and Texas A and M System Health Science Center, College of Medicine, Temple, Texas
| | - Gianfranco Alpini
- Research, Central Texas Veterans Health Care System, S and W and Texas A and M System Health Science Center, College of Medicine, Temple, Texas,Scott & White Digestive Disease Research Center, S and W and Texas A and M System Health Science Center, College of Medicine, Temple, Texas,Department of Medicine, Division Gastroenterology, S and W and Texas A and M System Health Science Center, College of Medicine, Temple, Texas
| | - Marco Marzioni
- Clinic of Gastroenterology and Hepatology, Università Politecnica delle Marche, Ancona, Italy
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Kobayashi H, Yoshida S, Sun YJ, Shirasawa N, Naito A. Gastric estradiol-17β (E2) and liver ERα correlate with serum E2 in the cholestatic male rat. J Endocrinol 2013; 219:39-49. [PMID: 23881936 DOI: 10.1530/joe-13-0156] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Cholestasis is associated with changes in hepatic cholesterol metabolism and serum estrogen levels. Ueyama and colleagues reported that the gastric estradiol-17β (E2) level in the portal vein is several times higher than that in the artery. This study aimed to clarify the relationships between gastric E2, hepatic estrogen receptor (ER) α and cholesterol metabolism in cholestatic male rats induced by bile duct ligation (BDL). After BDL, serum E2 levels in the portal vein and artery were measured by ELISA. The gene expression of gastric estrogen-synthesizing enzymes and various hepatic enzymes for cholesterol metabolism were measured by real-time RT-PCR, and gastric aromatase and hepatic ERα proteins were determined by immunohistochemistry and western blotting. Portal E2 levels increased by 4.9, 5.0, and 3.6 times that of controls at 2 days after BDL (BDL2d), BDL4d, and BDL7d respectively. The change in arterial E2 levels was positively correlated with that in the portal vein. Under these conditions, the expression of hepatic Ers1 (ERα) mRNA and protein was significantly reduced in a negative correlation with serum E2 levels in the portal vein after BDL. The expression of hepatic male-specific cytochrome P450 (CYP) genes Cyp2c55 and Cyp3a2 decreased and female-specific Cyp2c12 increased after BDL. It is postulated that the increase in gastric E2 levels, which occurs after BDL, results in the reduction of hepatic ERα, the elevation of arterial E2 level and leads to cholesterol metabolism becoming sex steroid dependent.
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Affiliation(s)
- Hiroto Kobayashi
- Department of Anatomy and Structural Science, Yamagata University Faculty of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan
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13
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Onori P, Mancinelli R, Franchitto A, Carpino G, Renzi A, Brozzetti S, Venter J, Francis H, Glaser S, Jefferson DM, Alpini G, Gaudio E. Role of follicle-stimulating hormone on biliary cyst growth in autosomal dominant polycystic kidney disease. Liver Int 2013; 33:914-25. [PMID: 23617956 PMCID: PMC4064944 DOI: 10.1111/liv.12177] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2012] [Accepted: 03/11/2013] [Indexed: 12/20/2022]
Abstract
BACKGROUND Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disorder characterized by the progressive development of renal and hepatic cysts. Follicle-stimulating hormone (FSH) has been demonstrated to be a trophic factor for biliary cells in normal rats and experimental cholestasis induced by bile duct ligation (BDL). AIMS To assess the effect of FSH on cholangiocyte proliferation during ADPKD using both in vivo and in vitro models. METHODS Evaluation of FSH receptor (FSHR), FSH, phospho-extracellular-regulated kinase (pERK) and c-myc expression in liver fragments from normal patients and patients with ADPKD. In vitro, we studied proliferating cell nuclear antigen (PCNA) and cAMP levels in a human immortalized, non-malignant cholangiocyte cell line (H69) and in an immortalized cell line obtained from the epithelium lining the hepatic cysts from the patients with ADPKD (LCDE) with or without transient silencing of the FSH gene. RESULTS Follicle-stimulating hormone is linked to the active proliferation of the cystic wall and to the localization of p-ERK and c-myc. This hormone sustains the biliary growth by activation of the cAMP/ERK signalling pathway. CONCLUSION These results showed that FSH has an important function in cystic growth acting on the cAMP pathway, demonstrating that it provides a target for medical therapy of hepatic cysts during ADPKD.
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Affiliation(s)
- Paolo Onori
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, University of Rome ‘Sapienza’, Rome, Italy
| | - Romina Mancinelli
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, University of Rome ‘Sapienza’, Rome, Italy
| | - Antonio Franchitto
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, University of Rome ‘Sapienza’, Rome, Italy,Eleonora Lorillard Spencer-Cenci Foundation, Rome, Italy
| | - Guido Carpino
- Department of Health Science, University of Rome ‘Foro Italico’, Rome, Italy
| | - Anastasia Renzi
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, University of Rome ‘Sapienza’, Rome, Italy
| | - Stefania Brozzetti
- Department of Surgical Sciences, University of Rome ‘Sapienza’, Rome, Italy
| | - Julie Venter
- Scott & White Digestive Disease Research Center, Central Texas Veterans Health Care System and Texas A&M Health Science Center, College of Medicine, Temple, TX, USA
| | - Heather Francis
- Scott & White Digestive Disease Research Center, Central Texas Veterans Health Care System and Texas A&M Health Science Center, College of Medicine, Temple, TX, USA
| | - Shannon Glaser
- Scott & White Digestive Disease Research Center, Central Texas Veterans Health Care System and Texas A&M Health Science Center, College of Medicine, Temple, TX, USA
| | | | - Gianfranco Alpini
- Scott & White Digestive Disease Research Center, Central Texas Veterans Health Care System and Texas A&M Health Science Center, College of Medicine, Temple, TX, USA
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, University of Rome ‘Sapienza’, Rome, Italy
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Tabibian JH, Macura SI, O'Hara SP, Fidler JL, Glockner JF, Takahashi N, Lowe VJ, Kemp BJ, Mishra PK, Tietz PS, Splinter PL, Trussoni CE, LaRusso NF. Micro-computed tomography and nuclear magnetic resonance imaging for noninvasive, live-mouse cholangiography. J Transl Med 2013; 93:733-43. [PMID: 23588707 PMCID: PMC3875307 DOI: 10.1038/labinvest.2013.52] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The cholangiopathies are a diverse group of biliary tract disorders, many of which lack effective treatment. Murine models are an important tool for studying their pathogenesis, but existing noninvasive methods for assessing biliary disease in vivo are not optimal. Here we report our experience with using micro-computed tomography (microCT) and nuclear magnetic resonance (MR) imaging to develop a technique for live-mouse cholangiography. Using mdr2 knockout (mdr2KO, a model for primary sclerosing cholangitis (PSC)), bile duct-ligated (BDL), and normal mice, we performed in vivo: (1) microCT on a Siemens Inveon PET/CT scanner and (2) MR on a Bruker Avance 16.4 T spectrometer, using Turbo Rapid Acquisition with Relaxation Enhancement, IntraGate Fast Low Angle Shot, and Half-Fourier Acquisition Single-shot Turbo Spin Echo methods. Anesthesia was with 1.5-2.5% isoflurane. Scans were performed with and without contrast agents (iodipamide meglumine (microCT), gadoxetate disodium (MR)). Dissection and liver histology were performed for validation. With microCT, only the gallbladder and extrahepatic bile ducts were visualized despite attempts to optimize timing, route, and dose of contrast. With MR, the gallbladder, extra-, and intrahepatic bile ducts were well-visualized in mdr2KO mice; the cholangiographic appearance was similar to that of PSC (eg, multifocal strictures) and could be improved with contrast administration. In BDL mice, MR revealed cholangiographically distinct progressive dilation of the biliary tree without ductal irregularity. In normal mice, MR allowed visualization of the gallbladder and extrahepatic ducts, but only marginal visualization of the diminutive intrahepatic ducts. One mouse died during microCT and MR imaging, respectively. Both microCT and MR scans could be obtained in ≤20 min. We, therefore, demonstrate that MR cholangiography can be a useful tool for longitudinal studies of the biliary tree in live mice, whereas microCT yields suboptimal duct visualization despite requiring contrast administration. These findings support further development and application of MR cholangiography to the study of mouse models of PSC and other cholangiopathies.
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Affiliation(s)
- James H Tabibian
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA
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15
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Siqueira OHK, Herani Filho B, Paula RED, Ascoli FO, Nóbrega ACLD, Carvalho ACG, Pires ARC, Gaglionone NC, Cunha KSG, Granjeiro JM. Tamoxifen decreases the myofibroblast count in the healing bile duct tissue of pigs. Clinics (Sao Paulo) 2013; 68:101-6. [PMID: 23420165 PMCID: PMC3552444 DOI: 10.6061/clinics/2013(01)oa16] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2012] [Accepted: 09/21/2012] [Indexed: 12/11/2022] Open
Abstract
OBJECTIVE The aim of this study was to evaluate the effect of oral tamoxifen treatment on the number of myofibroblasts present during the healing process after experimental bile duct injury. METHODS The sample consisted of 16 pigs that were divided into two groups (the control and study groups). Incisions and suturing of the bile ducts were performed in the two groups. Tamoxifen (20 mg/day) was administered only to the study group. The animals were sacrificed after 30 days. Quantification of myofibroblasts in the biliary ducts was made through immunohistochemistry analysis using anti-alpha smooth muscle actin of the smooth muscle antibody. Immunohistochemical quantification was performed using a digital image system. RESULTS In the animals treated with tamoxifen (20 mg/day), there was a significant reduction in immunostaining for alpha smooth muscle actin compared with the control group (0.1155 vs. 0.2021, p = 0.046). CONCLUSION Tamoxifen reduced the expression of alpha smooth muscle actin in the healing tissue after bile duct injury, suggesting a decrease in myofibroblasts in the scarred area of the pig biliary tract. These data suggest that tamoxifen could be used in the prevention of biliary tract stenosis after bile duct surgeries.
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16
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Yang F, Priester S, Onori P, Venter J, Renzi A, Franchitto A, Munshi MK, Wise C, Dostal DE, Marzioni M, Saccomanno S, Ueno Y, Gaudio E, Glaser S. Castration inhibits biliary proliferation induced by bile duct obstruction: novel role for the autocrine trophic effect of testosterone. Am J Physiol Gastrointest Liver Physiol 2011; 301:G981-91. [PMID: 21903763 PMCID: PMC3233786 DOI: 10.1152/ajpgi.00061.2011] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
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.
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Affiliation(s)
- Fuquan Yang
- Department of Medicine, Division of 1Gastroenterology and ,6Department of Hepatobiliary Surgery, Shengjing Hospital, China Medical University, Shenyang, Liaoning Province, China;
| | - Sally Priester
- Department of Medicine, Division of 1Gastroenterology and ,3Research & Education, Scott & White,
| | - Paolo Onori
- 7Experimental Medicine, University of L'Aquila, L'Aquila;
| | - Julie Venter
- Department of Medicine, Division of 1Gastroenterology and
| | - Anastasia Renzi
- Department of Medicine, Division of 1Gastroenterology and ,10Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, University of Rome “La Sapienza”, Rome; Fondazione Eleonora Lorillard Spencer-Cenci, Rome;
| | - Antonio Franchitto
- 10Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, University of Rome “La Sapienza”, Rome; Fondazione Eleonora Lorillard Spencer-Cenci, Rome; ,11Institute of Food and Radiation Safety, Dhaka, Bangladesh
| | - Md Kamruzzaman Munshi
- Department of Medicine, Division of 1Gastroenterology and ,11Institute of Food and Radiation Safety, Dhaka, Bangladesh
| | - Candace Wise
- Department of Medicine, Division of 1Gastroenterology and
| | - David E. Dostal
- 2Molecular Cardiology, Scott & White and Texas A&M Health Science Center, College of Medicine, ,5Central Texas Veterans Health Care System, Temple, Texas;
| | - Marco Marzioni
- 8Department of Gastroenterology, Università Politecnica delle Marche, Ancona, Italy,
| | - Stefania Saccomanno
- 8Department of Gastroenterology, Università Politecnica delle Marche, Ancona, Italy,
| | - Yoshiyuki Ueno
- 9Division of Gastroenterology, Tohoku Graduate University School of Medicine, Sendai, Japan; and
| | - Eugenio Gaudio
- 10Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, University of Rome “La Sapienza”, Rome; Fondazione Eleonora Lorillard Spencer-Cenci, Rome;
| | - Shannon Glaser
- Department of Medicine, Division of 1Gastroenterology and ,4Scott & White Digestive Disease Research Center, and ,5Central Texas Veterans Health Care System, Temple, Texas;
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17
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Munshi MK, Priester S, Gaudio E, Yang F, Alpini G, Mancinelli R, Wise C, Meng F, Franchitto A, Onori P, Glaser SS. Regulation of biliary proliferation by neuroendocrine factors: implications for the pathogenesis of cholestatic liver diseases. THE AMERICAN JOURNAL OF PATHOLOGY 2011; 178:472-84. [PMID: 21281779 DOI: 10.1016/j.ajpath.2010.09.043] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/15/2010] [Revised: 08/23/2010] [Accepted: 09/02/2010] [Indexed: 12/15/2022]
Abstract
The proliferation of cholangiocytes occurs during the progression of cholestatic liver diseases and is critical for the maintenance and/or restoration of biliary mass during bile duct damage. The ability of cholangiocytes to proliferate is important in many different human pathologic conditions. Recent studies have brought to light the concept that proliferating cholangiocytes serve as a unique neuroendocrine compartment in the liver. During extrahepatic cholestasis and other pathologic conditions that trigger ductular reaction, proliferating cholangiocytes acquire a neuroendocrine phenotype. Cholangiocytes have the capacity to secrete and respond to a variety of hormones, neuropeptides, and neurotransmitters, regulating their surrounding cell functions and proliferative activity. In this review, we discuss the regulation of cholangiocyte growth by neuroendocrine factors in animal models of cholestasis and liver injury, which includes a discussion of the acquisition of neuroendocrine phenotypes by proliferating cholangiocytes and how this relates to cholangiopathies. We also review what is currently known about the neuroendocrine phenotypes of cholangiocytes in human cholestatic liver diseases (ie, cholangiopathies) that are characterized by ductular reaction.
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19
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Mancinelli R, Onori P, DeMorrow S, Francis H, Glaser S, Franchitto A, Carpino G, Alpini G, Gaudio E. Role of sex hormones in the modulation of cholangiocyte function. World J Gastrointest Pathophysiol 2010; 1:50-62. [PMID: 21607142 PMCID: PMC3097944 DOI: 10.4291/wjgp.v1.i2.50] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2010] [Revised: 05/28/2010] [Accepted: 06/04/2010] [Indexed: 02/06/2023] Open
Abstract
Over the last years, cholangiocytes, the cells that line the biliary tree, have been considered an important object of study for their biological properties which involves bile formation, proliferation, injury repair, fibrosis and angiogenesis. Cholangiocyte proliferation occurs in all pathologic conditions of liver injury where it is associated with inflammation and regeneration. During these processes, biliary cells start to secrete different cytokines, growth factors, neuropeptides and hormones which represent potential mechanisms for cross talk with other liver cells. Several studies suggest that hormones, and in particular, sex hormones, play a fundamental role in the modulation of the growth of this compartment in the injured liver which functionally conditions the progression of liver disease. Understanding the mechanisms of action and the intracellular pathways of these compounds on cholangiocyte pathophysiology will provide new potential strategies for the management of chronic liver diseases. The purpose of this review is to summarize the recent findings on the role of sex hormones in cholangiocyte proliferation and biology.
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20
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Torrice A, Cardinale V, Gatto M, Semeraro R, Napoli C, Onori P, Alpini G, Gaudio E, Alvaro D. Polycystins play a key role in the modulation of cholangiocyte proliferation. Dig Liver Dis 2010; 42:377-85. [PMID: 19897428 DOI: 10.1016/j.dld.2009.09.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2009] [Revised: 09/13/2009] [Accepted: 09/20/2009] [Indexed: 12/11/2022]
Abstract
BACKGROUND Polycystin-1 and -2 (PC-1 and PC-2) are critical components of primary cilia, which act as mechanosensors and drive cell response to injury. PC-1 activation involves the cleavage/processing of PC-1 cytoplasmic tail, driven by regulated intramembrane proteolysis or ubiquitine/proteasome, translocation in the nucleus and activation of transcription factors. Mutations of PC-1 or PC-2 occur in polycystic liver where cholangiocyte proliferation is enhanced. AIM We evaluated the involvement of PC-1 and PC-2 in modulating cholangiocyte proliferation. METHODS We investigated rat cholangiocytes induced to proliferate by 17beta-oestradiol. Proliferation was evaluated by PCNA immunoblotting or [(3)H]-thymidine incorporation into DNA. PC-1 silencing was performed by siRNA, while inhibition of regulated intramembrane proteolysis or proteasome by gamma-secretase inhibitor, leupeptin or MG115. RESULTS Cholangiocyte proliferation was associated with decreased PC-1 and PC-2 expression, which was inversely correlated with enhanced PCNA. The selective silencing of PC-1 induced activation of cholangiocyte proliferation in association with decreased PC-1 expression. Two different regulated intramembrane proteolysis inhibitors, gamma-secretase-inhibitor and leupeptin, and the proteasome inhibitor, MG115, abolished the 17beta-oestradiol proliferative effect. CONCLUSIONS PC-1 and PC-2 play a major role as modulators of cholangiocyte proliferation suggesting that primary cilia may act as sensors of cell injury driving, when activated, a proliferative cholangiocyte response to trigger the reparative processes.
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Affiliation(s)
- Alessia Torrice
- Division of Gastroenterology, University of Rome, Sapienza, Rome, Italy
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21
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Clinical implications of novel aspects of biliary pathophysiology. Dig Liver Dis 2010; 42:238-44. [PMID: 20167547 DOI: 10.1016/j.dld.2010.01.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2009] [Revised: 01/11/2010] [Accepted: 01/11/2010] [Indexed: 12/11/2022]
Abstract
Cholangiocytes are the epithelial cells that line the biliary tree; they are the target of chronic diseases termed cholangiopathies, which represent a daily challenge for clinicians, since definitive medical treatments are not available yet. It is generally accepted that the progression of injury in the course of cholangiopathies, and promotion and progression of cholangiocarcinoma are at least in part due to the failure of the cholangiocytes' mechanisms of adaptation to injury. Recently, several studies on the pathophysiology of the biliary epithelium have shed some light on the mechanisms that govern cholangiocyte response to injury. These studies provide novel information to help interpret some of the clinical aspects of cholangiopathies and cholangiocarcinoma; the purpose of this review is thus to describe some of these novel findings, focusing on their significance from a clinical perspective.
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22
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Darwiche H, Petersen BE. Biology of the adult hepatic progenitor cell: "ghosts in the machine". PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2010; 97:229-49. [PMID: 21074735 PMCID: PMC3122078 DOI: 10.1016/b978-0-12-385233-5.00008-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
This chapter reviews some of the basic biological principles governing adult progenitor cells of the liver and the mechanisms by which they operate. If scientists were better able to understand the conditions that govern stem cell mechanics in the liver, it may be possible to apply that understanding in a clinical setting for use in the treatment or cure of human pathologies. This chapter gives a basic introduction to hepatic progenitor cell biology and explores what is known about progenitor cell-mediated liver regeneration. We also discuss the putative stem cell niche in the liver, as well as the signaling pathways involved in stem cell regulation. Finally, the isolation and clinical application of stem cells to human diseases is reviewed, along with the current thoughts on the relationship between stem cells and cancer.
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Affiliation(s)
- Houda Darwiche
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, Florida, USA
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Gaudio E, Carpino G, Cardinale V, Franchitto A, Onori P, Alvaro D. New insights into liver stem cells. Dig Liver Dis 2009; 41:455-62. [PMID: 19403350 DOI: 10.1016/j.dld.2009.03.009] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2009] [Accepted: 03/22/2009] [Indexed: 12/11/2022]
Abstract
Hepatic progenitor cells are bi-potential stem cells residing in human and animal livers that are able to differentiate towards the hepatocytic and the cholangiocytic lineages. In adult livers, hepatic progenitor cells are quiescent stem cells with a low proliferating rate, representing a reserve compartment that is activated only when the mature epithelial cells of the liver are continuously damaged or inhibited in their replication, or in cases of severe cell loss. Hepatic progenitor cell activation has been described in various acute and chronic liver diseases. Their niche is composed by numerous cells such as Hepatic Stellate Cells, endothelial cells, hepatocytes, cholangiocytes, Kupffer cells, pit cells and inflammatory cells. All these cells, numerous hormones and growth factors could interact and cross-talk with progenitor cells influencing their proliferative and differentiative processes. Hepatic progenitor cells and their niche could represent, in the near future, a target for therapeutic approaches to liver disease based on cell-specific drug delivery systems. Isolation and transplantation of hepatic progenitor cells could represent a new approach for therapy of end-stage chronic liver diseases, as they offer many advantages to transplantation of mature hepatocytes. The possibility of applying stem cell therapy to liver diseases will represent a major goal in this field.
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Affiliation(s)
- E Gaudio
- Department of Human Anatomy, Sapienza University of Rome, Rome, Italy.
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24
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Fouassier L, Rosenberg P, Mergey M, Saubaméa B, Clapéron A, Kinnman N, Chignard N, Jacobsson-Ekman G, Strandvik B, Rey C, Barbu V, Hultcrantz R, Housset C. Ezrin-radixin-moesin-binding phosphoprotein (EBP50), an estrogen-inducible scaffold protein, contributes to biliary epithelial cell proliferation. THE AMERICAN JOURNAL OF PATHOLOGY 2009; 174:869-80. [PMID: 19234136 DOI: 10.2353/ajpath.2009.080079] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
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 up-regulation and intracellular redistribution in response to 17beta-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.
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Affiliation(s)
- Laura Fouassier
- INSERM, UMR_S 893, CdR Saint-Antoine, Faculté de Médecine Pierre et Marie Curie, site Saint-Antoine, 27, rue Chaligny, 75571 Paris cedex 12, France.
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25
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Abstract
Cholangiocyte proliferation is triggered during extrahepatic bile duct obstruction induced by bile duct ligation, which is a common in vivo model used for the study of cholangiocyte proliferation and liver fibrosis. The proliferative response of cholangiocytes during cholestasis is regulated by the complex interaction of several factors, including gastrointestinal hormones, neuroendocrine hormones and autocrine or paracrine signalling mechanisms. Activation of biliary proliferation (ductular reaction) is thought to have a key role in the initiation and progression of liver fibrosis. The first part of this review provides an overview of the primary functions of cholangiocytes in terms of secretin-stimulated bicarbonate secretion--a functional index of cholangiocyte growth. In the second section, we explore the important regulators, both inhibitory and stimulatory, that regulate the cholangiocyte proliferative response during cholestasis. We discuss the role of proliferating cholangiocytes in the induction of fibrosis either directly via epithelial mesenchymal transition or indirectly via the activation of other liver cell types. The possibility of targeting cholangiocyte proliferation as potential therapy for reducing and/or preventing liver fibrosis, and future avenues for research into how cholangiocytes participate in the process of liver fibrogenesis are described.
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Marzioni M, Fava G, Alvaro D, Alpini G, Benedetti A. Control of cholangiocyte adaptive responses by visceral hormones and neuropeptides. Clin Rev Allergy Immunol 2009; 36:13-22. [PMID: 18548352 PMCID: PMC2628969 DOI: 10.1007/s12016-008-8090-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Cholangiocytes, the epithelial cells lining the biliary tree, are the target cells in several liver diseases, termed cholangiopathies. Cholangiopathies are a challenge for clinicians and an enigma for scientists, as the pathogenetic mechanisms by which they develop, and the therapeutic tools for these diseases are still undefined. Several studies demonstrate that many visceral hormones, neuropeptides, and neurotransmitters modulate the adaptive changes of cholangiocytes to chronic cholestatic injury. The aim of this review is to present the recent findings that contributed to clarify the role of visceral hormones and neuropeptides in the regulation of the pathophysiology of cholestasis. These studies helped to shed light on some aspects of cholangiocyte pathophysiology, revealing novel perspectives for the clinical managements of cholangiopathies.
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Affiliation(s)
- Marco Marzioni
- Department of Gastroenterology, Università Politecnica delle Miarche, Nuovo Polo Didattico, III piano, Via Tronto 10, 60020, Ancona, Italy.
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Glaser S, DeMorrow S, Francis H, Ueno Y, Gaudio E, Vaculin S, Venter J, Franchitto A, Onori P, Vaculin B, Marzioni M, Wise C, Pilanthananond M, Savage J, Pierce L, Mancinelli R, Alpini G. Progesterone stimulates the proliferation of female and male cholangiocytes via autocrine/paracrine mechanisms. Am J Physiol Gastrointest Liver Physiol 2008; 295:G124-G136. [PMID: 18511743 PMCID: PMC2494724 DOI: 10.1152/ajpgi.00536.2007] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2007] [Accepted: 05/22/2008] [Indexed: 01/31/2023]
Abstract
During cholestatic liver diseases, cholangiocytes express neuroendocrine phenotypes and respond to a number of hormones and neuropeptides by paracrine and autocrine mechanisms. We examined whether the neuroendocrine hormone progesterone is produced by and targeted to cholangiocytes, thereby regulating biliary proliferation during cholestasis. Nuclear (PR-A and PR-B) and membrane (PRGMC1, PRGMC2, and mPRalpha) progesterone receptor expression was evaluated in liver sections and cholangiocytes from normal and bile duct ligation (BDL) rats, and NRC cells (normal rat cholangiocyte line). In vivo, normal rats were chronically treated with progesterone for 1 wk, or immediately after BDL, rats were treated with a neutralizing progesterone antibody for 1 wk. Cholangiocyte growth was measured by evaluating the number of bile ducts in liver sections. The expression of the progesterone synthesis pathway was evaluated in liver sections, cholangiocytes and NRC. Progesterone secretion was evaluated in supernatants from normal and BDL cholangiocytes and NRC. In vitro, NRC were stimulated with progesterone and cholangiocyte supernatants in the presence or absence of antiprogesterone antibody. Aminoglutethimide was used to block progesterone synthesis. Cholangiocytes and NRC express the PR-B nuclear receptor and PRGMC1, PRGMC2, and mPRalpha. In vivo, progesterone increased the number of bile ducts of normal rats, whereas antiprogesterone antibody inhibited cholangiocyte growth stimulated by BDL. Normal and BDL cholangiocytes expressed the biosynthetic pathway for and secrete progesterone. In vitro, 1) progesterone increased NRC proliferation; 2) cholangiocyte supernatants increased NRC proliferation, which was partially inhibited by preincubation with antiprogesterone; and 3) inhibition of progesterone steroidogenesis prevented NRC proliferation. In conclusion, progesterone may be an important autocrine/paracrine regulator of cholangiocyte proliferation.
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Affiliation(s)
- Shannon Glaser
- Department of Medicine, Scott & White Hospital and Texas A&M University System Health Science Center, College of Medicine, Temple, Texas 76504, USA.
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28
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Carotti S, Morini S, Corradini SG, Burza MA, Molinaro A, Carpino G, Merli M, De Santis A, Muda AO, Rossi M, Attili AF, Gaudio E. Glial fibrillary acidic protein as an early marker of hepatic stellate cell activation in chronic and posttransplant recurrent hepatitis C. Liver Transpl 2008; 14:806-14. [PMID: 18508359 DOI: 10.1002/lt.21436] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Activated alpha-smooth muscle actin (alpha-SMA)-positive hepatic stellate cells (HSCs) are pericytes responsible for fibrosis in chronic liver injury. The glial fibrillary acidic protein (GFAP), commonly expressed by astrocytes in the central nervous system, is expressed in vivo in the liver in a subpopulation of quiescent stellate cells. In the rat, increased GFAP expression in the acute response to injury and down-regulation in the chronic response have been observed, whereas reports concerning GFAP expression in human liver are still conflicting. We investigated the utility of GFAP compared to alpha-SMA as an immunohistochemical marker of early activated HSCs in chronic and posttransplant recurrent hepatitis C and correlated GFAP expression with vascular remodeling and fibrosis progression. With immunohistochemistry and a semiquantitative scoring system, the expression of GFAP and alpha-SMA in HSCs and the microvessel density were analyzed in biopsies from normal livers obtained from cadaveric donors [donor liver (DL); n = 21] and from livers from posttransplant hepatitis C virus recurrent hepatitis (HCV-PTR) patients (n = 19), hepatitis C virus chronic hepatitis (HCV-CH) patients, (n = 12), and hepatitis C virus cirrhosis (HCV-C) patients (n = 16). The percentage of alpha-SMA-positive HSCs was significantly higher in the HCV-PTR, HCV-CH, and HCV-C groups compared to the DL group (P < 0.01). The percentage of GFAP-positive HSCs was significantly higher in the HCV-PTR group compared to the DL, HCV-C (P < 0.01), and HCV-CH (P < 0.05) groups and in the HCV-CH group compared to the DL group (P < 0.01), inversely correlating with the extent of fibrosis and microvessel density (P < 0.01). In the HCV-PTR group, the percentage of GFAP-positive HSCs correlated with fibrosis progression (P < 0.01). In conclusion, GFAP could represent a useful marker of early activation of HSCs in HCV-CH and seems to predict fibrosis progression in HCV-PTR.
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Affiliation(s)
- Simone Carotti
- Department of Human Anatomy, University of Rome La Sapienza, Italy, Rome
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DeMorrow S, Francis H, Gaudio E, Ueno Y, Venter J, Onori P, Franchitto A, Vaculin B, Vaculin S, Alpini G. Anandamide inhibits cholangiocyte hyperplastic proliferation via activation of thioredoxin 1/redox factor 1 and AP-1 activation. Am J Physiol Gastrointest Liver Physiol 2008; 294:G506-19. [PMID: 18096608 DOI: 10.1152/ajpgi.00304.2007] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The endocannabinoid system regulates various aspects of hepatic fibrosis; however, nothing is known about its role in regulating cholangiocyte proliferation and function. We evaluated the effects of anandamide (AEA) on cholangiocyte proliferation and explored the effects of AEA on the thioredoxin 1 (TRX1)/redox factor 1 (Ref1)/activator protein-1 (AP-1) pathway. Mice underwent bile duct ligation (BDL) and were infused with AEA for 3 days postsurgery. Proliferation and apoptosis were evaluated in liver sections. Effects of in vitro AEA treatment on cholangiocyte proliferation and apoptosis were studied in purified cholangiocytes. The relative expression of cannabinoid receptors was also assessed in liver sections and cholangiocytes. mRNA expression of the cannabinoid receptors Cb1 and VR1 was decreased after BDL, whereas there was an upregulation of Cb2 mRNA. AEA decreased cholangiocyte growth and induced accumulation of reactive oxygen species, upregulation of TRX1, Ref1, c-Fos, and c-Jun expression, increased nuclear localization of TRX1, and increased AP-1 transcriptional activity. Specific knockdown of TRX1 or Ref1 expression ablated the AP-1 transcriptional activity and AEA-induced cell death but not expression of c-Fos and c-Jun. Knockdown of c-Fos and c-Jun expression also ablated AEA-induced apoptosis. We conclude that AEA suppresses cholangiocyte proliferation during cholestasis via a Cb2-dependent mechanism. Modulation of the endocannabinoid system may be important in the treatment of cholangiopathies.
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Affiliation(s)
- Sharon DeMorrow
- Division of Research and Education, Scott & White Hospital, Temple, TX 76504, USA.
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Alvaro D, Onori P, Alpini G, Franchitto A, Jefferson DM, Torrice A, Cardinale V, Stefanelli F, Mancino MG, Strazzabosco M, Angelico M, Attili A, Gaudio E. Morphological and functional features of hepatic cyst epithelium in autosomal dominant polycystic kidney disease. THE AMERICAN JOURNAL OF PATHOLOGY 2008; 172:321-32. [PMID: 18202196 DOI: 10.2353/ajpath.2008.070293] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
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 17beta-estradiol and IGF1 and when exposed to human cyst fluid. ER or IGF1-R antagonists inhibited the proliferative effect of serum readmission, cyst fluid, 17beta-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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Affiliation(s)
- Domenico Alvaro
- Department of Clinical Medicine, University of Rome Sapienza, via R. Rossellini 51, 00137 Rome, Italy. domenico.alvaro@uniroma1
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31
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Prolactin stimulates the proliferation of normal female cholangiocytes by differential regulation of Ca2+-dependent PKC isoforms. BMC PHYSIOLOGY 2007; 7:6. [PMID: 17640386 PMCID: PMC1939715 DOI: 10.1186/1472-6793-7-6] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/05/2007] [Accepted: 07/19/2007] [Indexed: 01/09/2023]
Abstract
Background Prolactin promotes proliferation of several cells. Prolactin receptor exists as two isoforms: long and short, which activate different transduction pathways including the Ca2+-dependent PKC-signaling. No information exists on the role of prolactin in the regulation of the growth of female cholangiocytes. The rationale for using cholangiocytes from female rats is based on the fact that women are preferentially affected by specific cholangiopathies including primary biliary cirrhosis. We propose to evaluate the role and mechanisms of action by which prolactin regulates the growth of female cholangiocytes. Results Normal cholangiocytes express both isoforms (long and short) of prolactin receptors, whose expression increased following BDL. The administration of prolactin to normal female rats increased cholangiocyte proliferation. In purified normal female cholangiocytes, prolactin stimulated cholangiocyte proliferation, which was associated with increased [Ca2+]i levels and PKCβ-I phosphorylation but decreased PKCα phosphorylation. Administration of an anti-prolactin antibody to BDL female rats decreased cholangiocyte proliferation. Normal female cholangiocytes express and secrete prolactin, which was increased in BDL rats. The data show that prolactin stimulates normal cholangiocyte growth by an autocrine mechanism involving phosphorylation of PKCβ-I and dephosphorylation of PKCα. Conclusion We suggest that in female rats: (i) prolactin has a trophic effect on the growth of normal cholangiocytes by phosphorylation of PKCβ-I and dephosphorylation of PKCα; and (iii) cholangiocytes express and secrete prolactin, which by an autocrine mechanism participate in regulation of cholangiocyte proliferation. Prolactin may be an important therapeutic approach for the management of cholangiopathies affecting female patients.
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Alvaro D, Mancino MG, Glaser S, Gaudio E, Marzioni M, Francis H, Alpini G. Proliferating cholangiocytes: a neuroendocrine compartment in the diseased liver. Gastroenterology 2007; 132:415-31. [PMID: 17241889 DOI: 10.1053/j.gastro.2006.07.023] [Citation(s) in RCA: 224] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2006] [Accepted: 07/12/2006] [Indexed: 12/16/2022]
Abstract
In the last 15 years, the intrahepatic biliary tree has become the object of extensive studies, which highlighted the extraordinary biologic properties of cholangiocytes involved in bile formation, proliferation, injury repair, fibrosis, angiogenesis, and regulation of blood flow. Proliferation is a "typical" property of cholangiocytes and is key as a mechanism of repair responsible for maintaining the integrity of the biliary tree. Cholangiocyte proliferation occurs virtually in all pathologic conditions of liver injury where it is associated with inflammation, regeneration, and repair, thus conditioning the evolution of liver damage. Interestingly, proliferating cholangiocytes acquire the phenotype of neuroendocrine cells, and secrete different cytokines, growth factors, neuropeptides, and hormones, which represent potential mechanisms for cross talk with other liver cells. Many studies suggest the generation of a neuroendocrine compartment in the injured liver, mostly constituted by cells with cholangiocyte features, which functionally conditions the progression of liver disease. These insights on cholangiocyte pathophysiology will provide new potential strategies for the management of chronic liver diseases. The purpose of this review is to summarize the recent findings on the mechanisms regulating cholangiocyte proliferation and the significance of the neuroendocrine regulation of cholangiocyte biology.
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Affiliation(s)
- Domenico Alvaro
- Division of Gastroenterology, Department of Clinical Medicine, University La Sapienza, via R. Rossellini 51, 00137 Rome, Italy.
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33
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Alvaro D, Barbaro B, Franchitto A, Onori P, Glaser SS, Alpini G, Francis H, Marucci L, Sterpetti P, Ginanni-Corradini S, Onetti Muda A, Dostal DE, De Santis A, Attili AF, Benedetti A, Gaudio E. Estrogens and insulin-like growth factor 1 modulate neoplastic cell growth in human cholangiocarcinoma. THE AMERICAN JOURNAL OF PATHOLOGY 2006; 169:877-88. [PMID: 16936263 PMCID: PMC1698823 DOI: 10.2353/ajpath.2006.050464] [Citation(s) in RCA: 117] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
We investigated the expression of estrogen receptors (ERs), insulin-like growth factor 1 (IGF-1), and IGF-1R (receptor) in human cholangiocarcinoma and cholangiocarcinoma cell lines (HuH-28, TFK-1, Mz-ChA-1), evaluating the role of estrogens and IGF-1 in the modulation of neoplastic cell growth. ER-alpha, ER-beta, IGF-1, and IGF-1R were expressed (immunohistochemistry) in all biopsies (18 of 18) of intrahepatic cholangiocarcinoma. ER-alpha was expressed (Western blot) only by the HuH-28 cell line (intrahepatic cholangiocarcinoma), whereas ER-beta, IGF-1, and IGF-1R were expressed in the three cell lines examined. In serum-deprived HuH-28 cells, serum readmission induced stimulation of cell proliferation that was inhibited by ER and IGF-1R antagonists. 17beta-Estradiol and IGF-1 stimulated proliferation of HuH-28 cells to a similar extent to that of MCF7 (breast cancer) but greater than that of TFK-1 and Mz-ChA-1, inhibiting apoptosis and exerting additive effects. These effects of 17beta-estradiol and IGF-1 were associated with enhanced protein expression of ER-alpha, phosphorylated (p)-ERK1/2 and pAKT but with decreased expression of ER-beta. Finally, transfection of IGF-1R anti-sense oligonucleotides in HuH-28 cells markedly decreased cell proliferation. In conclusion, human intrahepatic cholangiocarcinomas express receptors for estrogens and IGF-1, which cooperate in the modulation of cell growth and apoptosis. Modulation of ER and IGF-1R could represent a strategy for the management of cholangiocarcinoma.
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Affiliation(s)
- Domenico Alvaro
- Department of Clinical Medicine, Division of Gastroenterology, University of Rome, via R. Rossellini 51, 00137 Rome, Italy. domenico.alvaro@uniroma1
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He XS, Ansari AA, Ridgway WM, Coppel RL, Gershwin ME. New insights to the immunopathology and autoimmune responses in primary biliary cirrhosis. Cell Immunol 2006; 239:1-13. [PMID: 16765923 DOI: 10.1016/j.cellimm.2006.04.006] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2006] [Revised: 04/19/2006] [Accepted: 04/20/2006] [Indexed: 01/07/2023]
Abstract
Primary biliary cirrhosis (PBC) is an autoimmune liver disease with profound changes in different compartments of the immune system, including those involved in innate, and adaptive immunity. New data from epidemiological studies of PBC have reinforced the thesis that the cause for this relatively uncommon disease is likely to be a combination of both environmental factors and a susceptible genetic predisposition. Recent findings of abnormalities of the innate immune system in PBC suggest that they may serve as links between the environmental factors and the early events in PBC development. Viral and bacterial infections as well as xenobiotics are some of the potential environmental factors that have been implicated in this complex process. Identification of the etiological factors for PBC will point to new preventive or therapeutic treatments.
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Affiliation(s)
- Xiao-Song He
- Division of Rheumatology, Allergy and Clinical Immunology, School of Medicine, University of California, Davis, USA
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35
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Marzioni M, Fava G, Benedetti A. Nervous and Neuroendocrine regulation of the pathophysiology of cholestasis and of biliary carcinogenesis. World J Gastroenterol 2006; 12:3471-3480. [PMID: 16773704 PMCID: PMC4087563 DOI: 10.3748/wjg.v12.i22.3471] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2006] [Revised: 02/06/2006] [Accepted: 02/18/2006] [Indexed: 02/06/2023] Open
Abstract
Cholangiocytes, the epithelial cells lining the biliary ducts, are the target cells in several liver diseases. Cholangiopathies and cholangiocarcinoma generate interest in many scientists since the genesis. The developing mechanisms, and the therapeutic tools of these diseases are still undefined. Several studies demonstrate that many hormones, neuropeptides and neurotransmitters regulate malignant and non-malignant cholangiocyte pathophysiology in the course of chronic biliary diseases. The aim of this review is to present the findings of several studies published in the recent years that contributed to clarifying the role of nervous and neuroendocrine regulation of the pathophysiologic events associated with cholestasis and cholangiocarcinoma development. This manuscript is organized into two parts. The first part offers an overview of the innervation of the liver and the origin of neuroendocrine hormones, neurotransmitters and neuropeptides affecting cholangiocyte function and metabolism. The first section also reviews the effects played by several neuroendocrine hormones and nervous system on cholangiocyte growth, survival and functional activity in the course of cholestasis. In the second section, we summarize the results of some studies describing the role of nervous system and neuroendocrine hormones in the regulation of malignant cholangiocyte growth.
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Affiliation(s)
- Marco Marzioni
- Department of Gastroenterology, Università Politecnica delle Marche, Nuovo Polo Didattico, III piano, Via Tronto 10, 60020 Ancona, Italy.
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Glaser S, Francis H, Demorrow S, Lesage G, Fava G, Marzioni M, Venter J, Alpini G. Heterogeneity of the intrahepatic biliary epithelium. World J Gastroenterol 2006; 12:3523-3536. [PMID: 16773709 PMCID: PMC4087568 DOI: 10.3748/wjg.v12.i22.3523] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2006] [Revised: 05/10/2006] [Accepted: 05/18/2006] [Indexed: 02/06/2023] Open
Abstract
The objectives of this review are to outline the recent findings related to the morphological heterogeneity of the biliary epithelium and the heterogeneous pathophysiological responses of different sized bile ducts to liver gastrointestinal hormones and peptides and liver injury/toxins with changes in apoptotic, proliferative and secretory activities. The knowledge of biliary function is rapidly increasing because of the recognition that biliary epithelial cells (cholangiocytes) are the targets of human cholangiopathies, which are characterized by proliferation/damage of bile ducts within a small range of sizes. The unique anatomy, morphology, innervation and vascularization of the biliary epithelium are consistent with function of cholangiocytes within different regions of the biliary tree. The in vivo models [e.g., bile duct ligation (BDL), partial hepatectomy, feeding of bile acids, carbon tetrachloride (CCl4) or alpha-naphthylisothiocyanate (ANIT)] and the in vivo experimental tools [e.g., freshly isolated small and large cholangiocytes or intrahepatic bile duct units (IBDU) and primary cultures of small and large murine cholangiocytes] have allowed us to demonstrate the morphological and functional heterogeneity of the intrahepatic biliary epithelium. These models demonstrated the differential secretory activities and the heterogeneous apoptotic and proliferative responses of different sized ducts. Similar to animal models of cholangiocyte proliferation/injury restricted to specific sized ducts, in human liver diseases bile duct damage predominates specific sized bile ducts. Future studies related to the functional heterogeneity of the intrahepatic biliary epithelium may disclose new pathophysiological treatments for patients with cholangiopathies.
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Affiliation(s)
- Shannon Glaser
- Department of Medicine, Division of R&E, Scott and White Memorial Hospital and The Texas A&M University System Health Science Center College of Medicine, MRB, 702 South West H.K. Dodgen Loop, Temple, Texas 76504, USA.
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Alvaro D, Mancino MG, Onori P, Franchitto A, Alpini G, Francis H, Glaser S, Gaudio E. Estrogens and the pathophysiology of the biliary tree. World J Gastroenterol 2006; 12:3537-45. [PMID: 16773710 PMCID: PMC4087569 DOI: 10.3748/wjg.v12.i22.3537] [Citation(s) in RCA: 94] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The scientific framework concerning estrogen effects on different tissues has expanded enormously during the last decades, when estrogen receptor (ER) subtypes were identified. Estrogens are not only essential for the female reproductive system, but they also control fundamental functions in other tissues including the cardiovascular system, bone, brain and liver. Recently, estrogens have been shown to target the biliary tree, where they modulate the proliferative and secretory activities of cholangiocytes, the epithelial cells lining bile ducts. By acting on both estrogen receptors (ER-α) and (ER-β) subtypes, and by activating either genomic or non-genomic pathways, estrogens play a key role in the complex loop of growth factors and cytokines, which modulates the proliferative response of cholangiocytes to damage. Specifically, estrogens activate intracellular signalling cascades [ERK1/2 (extracellular regulated kinases 1/2, PI3- kinase/AKT (phosphatidylinositol-3’ kinase/AKT)] typical of growth factors such as insulin like growth factor (IGF1), nerve growth factor (NGF) and vascular endothelial growth factor (VEGF), thus potentiating their action. In addition, estrogens stimulate the secretion of different growth factors in proliferating cholangiocytes. This review specifically deals with the recent advances related to the role and mechanisms by which estrogens modulate cholangiocyte functions in normal and pathological conditions.
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Affiliation(s)
- Domenico Alvaro
- Division of Gastroenterology, University of Rome, La Sapienza, via R. Rossellini 51, 00137 Rome, Italy.
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Svegliati-Baroni G, Ghiselli R, Marzioni M, Alvaro D, Mocchegiani F, Saccomanno S, Sisti V, Ugili L, Orlando F, Alpini G, Saba V, Benedetti A. Estrogens maintain bile duct mass and reduce apoptosis after biliodigestive anastomosis in bile duct ligated rats. J Hepatol 2006; 44:1158-1166. [PMID: 16481066 DOI: 10.1016/j.jhep.2005.10.032] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2005] [Revised: 10/05/2005] [Accepted: 10/14/2005] [Indexed: 02/05/2023]
Abstract
BACKGROUND/AIMS Disapperacence of bile ducts (ductopenia) represents the terminal, common stage of human cholangiopathies, and estrogens exert a major role in stimulating cholangiocyte proliferation. We thus evaluated whether estrogen administration protect from the bile duct loss induced by the biliary-digestive diversion in bile duct ligated (BDL) rats. METHODS After 3 weeks of BDL, rats were subjected to biliary-digestive diversion and treated with daily injections of 17beta-estradiol or a control solution. RESULTS Both after 7 and 14 days from the biliary-digestive diversion a marked increase of the number of apoptotic cholangiocytes was observed. In contrast, 17beta-estradiol significantly reduced cholangiocyte apoptosis. 17beta-estradiol also prevented the biliary-digestive diversion-induced loss of PCNA-positive cholangiocytes and of the bile duct mass. Biliary-digestive diversion determined a marked reduction of ERK1/2 phopsphorylation in cholangiocytes that was reversed by the administration of 17beta-estradiol. CONCLUSIONS This study indicates that estrogens prevent the increase of cholangiocyte apoptosis and loss of cholangiocyte proliferation induced by the biliary-digestive diversion in the BDL rat. In parallel, 17beta-estradiol also enhanced ERK1/2 phosphorylation, which is instead strongly reduced by the biliary-digestive diversion. These novel findings suggest that estrogens could prevent the evolution of cholangiopathies toward ductopenia.
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Affiliation(s)
- Gianluca Svegliati-Baroni
- Clinica di Gastroenterologia, Università Politecnica delle Marche, INRCA, IRCCS, Via Tronto, Ancona, 60020, Italy.
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Ricchi M, Bertolotti M, Anzivino C, Carulli L, Canedi I, Bormioli ML, Tiozzo R, Croce MA, Lonardo A, Carulli N, Loria P. 17 Beta-estradiol prevents cytotoxicity from hydrophobic bile acids in HepG2 and WRL-68 cell cultures. J Gastroenterol Hepatol 2006; 21:894-901. [PMID: 16704542 DOI: 10.1111/j.1440-1746.2006.04144.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
BACKGROUND Epidemiological and clinical studies suggest the possibility that estrogens might have a cytoprotective effect on the liver. The aim of the present study was to test the hypothesis that 17beta-estradiol (E2) prevents hepatocellular damage induced by deoxycholic acid (DCA), a hydrophobic bile acid. METHODS HepG2 cells were exposed for 24 h to DCA (350 micromol/L). Cell viability, aspartate aminotransferase and lactate dehydrogenase activity and apoptosis were measured as indices of cell toxicity. The effect of DCA was compared to that observed using either a hydrophilic bile acid, ursodeoxycholic acid (UDCA; 100 micromol/L), or E2 at different concentrations (1 nmol/L, 10 nmol/L, 50 nmol/L and 50 micromol/L) or mixtures of E2/DCA or UDCA/DCA. The same experiments were performed using WRL-68 cells that, at variance with HepG2, express a higher level of nuclear estrogen receptor. RESULTS High concentrations of E2 and UDCA prevented DCA-induced decrease in cell viability, increase in enzyme activity and apoptosis evaluated both by 4',6-diamidino-2-phenylindole dihydrochloride (DAPI) and TdT-mediated dUTP nick-end labeling (TUNEL) assays. In addition, DCA-related apoptosis, assessed by caspase activity, was also prevented by E2 (P < 0.01) in physiological (1-10 nmol/L) doses. The cytoprotective effects of E2 and UDCA was also observed in the WRL-68 cell line. CONCLUSIONS 17Beta-Estradiol prevents DCA-induced cell damage in HepG2 and WRL-68 cell lines to an extent comparable to UDCA. The hypothesis that the protective effect of E2 may be mediated by a mechanism that is nuclear estrogen receptor independent, deserves further verification.
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Affiliation(s)
- Matteo Ricchi
- Department of Internal Medicine, University of Modena and Reggio Emilia, Modena, Italy
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Alvaro D, Metalli VD, Alpini G, Onori P, Franchitto A, Barbaro B, Glaser SS, Francis H, Cantafora A, Blotta I, Attili AF, Gaudio E. The intrahepatic biliary epithelium is a target of the growth hormone/insulin-like growth factor 1 axis. J Hepatol 2005; 43:875-83. [PMID: 16083987 DOI: 10.1016/j.jhep.2005.04.011] [Citation(s) in RCA: 58] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2004] [Revised: 03/11/2005] [Accepted: 04/07/2005] [Indexed: 02/08/2023]
Abstract
BACKGROUND/AIMS We evaluated the role and mechanisms by which the GH/IGF1 axis modulates cholangiocyte proliferation. METHODS GH-receptors (GH-R), IGF1, IGFBP3 (binding protein 3), IGF1-R and receptor substrates (IRS) were evaluated in cholangiocytes of normal or bile duct-ligated (BDL) rat livers. The effects of GH and IGF1 on proliferation of normal quiescent cholangiocytes and the transduction pathways involved were investigated. RESULTS IGF1, GH-R, IGF1-R, IRS-1/2 were expressed in normal cholangiocytes and overexpressed in cholangiocytes proliferating after BDL which also secrete IGF1 in a higher amount than normal cells. IGFBP3, which may counter-regulate IGF1 effects, was decreased in BDL cholangiocytes. IGF1 promoted cholangiocyte proliferation in association with overexpression of p-IGF1R, IRS1, IRS-2, p-ERK1/2 and p-AKT. GH induced IGF1 expression and release in isolated cholangiocytes, and reproduced the effects of IGF1 but GH effects were abolished by IGF1-R blocking antibody, suggesting IGF1 as a mediator of GH. Finally, IGF1 and 17beta-estradiol reciprocally potentiated their proliferative effects on cholangiocytes, and by interacting at both receptor and post-receptor levels. CONCLUSIONS Cholangiocytes respond to GH with production and release of IGF1 that modulates cell proliferation by transduction pathways involving IGF1-R, IRS1/2 and both ERK and PI3-kinase pathways. The biliary epithelium is a target of GH/IGF1 liver axis.
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Affiliation(s)
- Domenico Alvaro
- Division of Gastroenterology, University of Rome, La Sapienza, Rome, Italy.
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Marzioni M, Glaser S, Francis H, Marucci L, Benedetti A, Alvaro D, Taffetani S, Ueno Y, Roskams T, Phinizy JL, Venter J, Fava G, Lesage GD, Alpini G. Autocrine/paracrine regulation of the growth of the biliary tree by the neuroendocrine hormone serotonin. Gastroenterology 2005; 128:121-137. [PMID: 15633129 DOI: 10.1053/j.gastro.2004.10.002] [Citation(s) in RCA: 97] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND & AIMS The biliary tree is the target of cholangiopathies that are chronic cholestatic liver diseases characterized by loss of proliferative response and enhanced apoptosis of cholangiocytes, the epithelial cells lining the biliary tree. The endogenous factors that regulate cholangiocyte proliferation are poorly understood. Therefore, we studied the role of the neuroendocrine hormone serotonin as a modulator of cholangiocyte proliferation. METHODS The presence of the serotonin 1A and 1B receptors on cholangiocytes was evaluated. We then tested whether the activation of such receptors by the administration of the selective agonists modifies cholangiocyte proliferation and functional activity both in vivo and in vitro. In addition, the intracellular signal mediating the serotonin receptor action in cholangiocytes was characterized. We studied the expression and secretion of serotonin by cholangiocytes and the effects of the neutralization of the secreted hormone on the growth of the biliary tree. RESULTS Cholangiocytes express the serotonin 1A and 1B receptors. Their activation markedly inhibits the growth and choleretic activity of the biliary tree in the bile duct-ligated rat, a model of chronic cholestasis. Such changes are mediated by enhanced d -myo-inositol 1,4,5-triphosphate/Ca 2+ /protein kinase C signaling and the consequent inhibition of the adenosine 3',5'-cyclic monophosphate/protein kinase A/Src/extracellular signal-regulated kinase 1/2 cascade. Cholangiocytes secrete serotonin, the blockage of which enhances cholangiocyte proliferation in the course of cholestasis. CONCLUSIONS We observed the existence of an autocrine loop based on serotonin that limits the growth of the biliary tree in the course of chronic cholestasis. Our novel findings might open new approaches for the management of cholangiopathies.
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Affiliation(s)
- Marco Marzioni
- Department of Medical Physiology, Scott & White Hospital, and Texas A&M University Health System Science Center, 702 Southwest H.K. Dodgen Loop, Temple, TX 76504, USA
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Alvaro D, Invernizzi P, Onori P, Franchitto A, De Santis A, Crosignani A, Sferra R, Ginanni-Corradini S, Mancino MG, Maggioni M, Attili AF, Podda M, Gaudio E. Estrogen receptors in cholangiocytes and the progression of primary biliary cirrhosis. J Hepatol 2004; 41:905-12. [PMID: 15645536 DOI: 10.1016/j.jhep.2004.08.022] [Citation(s) in RCA: 91] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND/AIMS Estrogen receptors (ER) in cholangiocytes of primary biliary cirrhosis (PBC) patients and their relationship with cell proliferation and death were evaluated. METHODS Liver biopsies from PBC patients with different histological stages were investigated by immunohistochemistry for ER-alpha and -beta, cytokeratin-19, proliferating cellular nuclear antigen (PCNA), Fas and terminal deoxynucleotide transferase end labelling (TUNEL). Normal livers and livers from primary sclerosing cholangitis and alcoholic cirrhosis were investigated as controls. RESULTS ER-alpha and -beta were observed in cholangiocytes of PBC patients but not in normal liver. In PBC, positivity for ER-beta was high (50-65 %) in all histological stages while, positivity for ER-alpha increased from 1% in stage I to 12 % in stage III (positivity correlated and co-localized in the same cell with PCNA). In stage IV of PBC, cholangiocytes were negative for ER-alpha in association with a lower PCNA positivity and with maximal degree of ductopenia. ER-alpha positivity in cholangiocytes of PBC patients was markedly lower than primary sclerosing cholangitis and alcoholic cirrhosis. CONCLUSIONS ER are expressed in PBC and other pathologies associated with cholangiocyte proliferation but not in normal subjects. The low expression of ER-alpha in PBC and their disappearance in the advanced histological stages suggests that an estrogenic deficiency could favour the evolution of this disease toward ductopenia.
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MESH Headings
- Apoptosis
- Bile Ducts, Intrahepatic/metabolism
- Bile Ducts, Intrahepatic/pathology
- Biomarkers/metabolism
- Case-Control Studies
- Cell Division
- Cholangitis, Sclerosing/metabolism
- Cholangitis, Sclerosing/pathology
- Cholangitis, Sclerosing/physiopathology
- Disease Progression
- Estrogen Receptor alpha/metabolism
- Estrogen Receptor beta/metabolism
- Humans
- Immunohistochemistry
- Liver/metabolism
- Liver/pathology
- Liver Cirrhosis, Alcoholic/metabolism
- Liver Cirrhosis, Alcoholic/pathology
- Liver Cirrhosis, Alcoholic/physiopathology
- Liver Cirrhosis, Biliary/metabolism
- Liver Cirrhosis, Biliary/pathology
- Liver Cirrhosis, Biliary/physiopathology
- Proliferating Cell Nuclear Antigen/metabolism
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Affiliation(s)
- Domenico Alvaro
- Division of Gastroenterology, Department of Clinical Medicine, University of Rome, La Sapienza, via R. Rossellini 51, 00137 Rome, Italy.
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Bergasa NV, Mason A, Floreani A, Heathcote J, Swain MG, Jones DEJ, Lindor KM, Bassendine MF, Worman HJ. Primary biliary cirrhosis: report of a focus study group. Hepatology 2004; 40:1013-20. [PMID: 15382160 DOI: 10.1002/hep.20446] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/07/2022]
Affiliation(s)
- Nora V Bergasa
- State University of New York, Downstate Medical Center, Brooklyn, NY 11203, USA.
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Abstract
Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease, which predominantly affects women. It is characterised histologically by necroinflammation of small intrahepatic bile ducts and biochemically by elevated serum alkaline phosphatase, levels of which at diagnosis predict survival. Ursodeoxycholic acid (UDCA) is the only treatment shown to improve liver biochemistry and survival. We report two patients with PBC who show a fall in serum alkaline phosphates levels whilst receiving tamoxifen therapy. Tamoxifen may exert this effect, which warrants further study, either via cholangiocyte estrogen receptors, inhibiting cholangiocyte proliferation and inducing apoptosis or by activating pregnane X receptor, analogous to the mode of action of UDCA.
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Affiliation(s)
- A Reddy
- Freeman Hospital Liver Unit, Newcastle upon Tyne Hospitals Trust, UK
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Invernizzi P, Alvaro D, Crosignani A, Gaudio E, Podda M. Tamoxifen in treatment of primary biliary cirrhosis. Hepatology 2004; 39:1175-6. [PMID: 15057925 DOI: 10.1002/hep.20164] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Tietz P, LaRusso NF. Cholangiocyte biology. Curr Opin Gastroenterol 2003; 19:264-9. [PMID: 15703567 DOI: 10.1097/00001574-200305000-00010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
Cholangiocytes are of considerable intrinsic biologic interest, particularly with regard to their roles in the transport of water, ions, and solutes, and to their heterogeneity and proliferative capacity. Cholangiocytes represent an important target of study in the cholangiopathies, a group of genetic developmental and acquired diseases of the liver. New biologic concepts continue to evolve through the use of experimental models (eg, knockout mice and selective gene silencing) and enhanced approaches to three-dimensional modeling and microscopy. The role of the cholangiocyte cytoskeleton in transport and intracellular trafficking has been recently recognized. These paradigms provide a framework for further understanding the mechanisms modulating normal cholangiocyte growth, transport, and signaling, and the abnormalities that result in disease.
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Affiliation(s)
- Pamela Tietz
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Medical School, and Foundation, Rochester, Minnesota 55905, USA
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Abstract
Further insights into the cellular and molecular mechanisms underlying hepatobiliary transport function and its regulation now permit a better understanding of the pathogenesis and treatment options of cholestatic liver diseases. Identification of the molecular basis of hereditary cholestatic syndromes will result in an improved diagnosis and management of these conditions. New insights into the pathogenesis of extrahepatic manifestations of cholestasis (eg, pruritus) have facilitated new treatment strategies. Important new studies have been published about the pathogenesis, clinical features, diagnosis, and treatment of primary biliary cirrhosis, primary sclerosing cholangitis, cholestasis of pregnancy, total parenteral nutrition-induced cholestasis, drug-induced cholestasis, and viral cholestatic syndromes.
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Affiliation(s)
- Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Karl-Franzens University, School of Medicine, Graz, Austria
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