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Bintee B, Banerjee R, Hegde M, Vishwa R, Alqahtani MS, Abbas M, Alqahtani A, Rangan L, Sethi G, Kunnumakkara AB. Exploring bile acid transporters as key players in cancer development and treatment: Evidence from preclinical and clinical studies. Cancer Lett 2025; 609:217324. [PMID: 39571783 DOI: 10.1016/j.canlet.2024.217324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 11/09/2024] [Accepted: 11/11/2024] [Indexed: 12/01/2024]
Abstract
Bile acid transporters (BATs) are integral membrane proteins belonging to various families, such as solute carriers, organic anion transporters, and ATP-binding cassette families. These transporters play a crucial role in bile acid transportation within the portal and systemic circulations, with expression observed in tissues, including the liver, kidney, and small intestine. Bile acids serve as signaling molecules facilitating the absorption and reabsorption of fats and lipids. Dysregulation of bile acid concentration has been implicated in tumorigenesis, yet the role of BATs in this process remains underexplored. Emerging evidence suggests that BATs may modulate various stages of cancer progression, including initiation, development, proliferation, metastasis, and tumor microenvironment regulation. Targeting BATs using siRNAs, miRNAs, and small compound inhibitors in preclinical models and their polymorphisms are well-studied for transporters like BSEP, MDR1, MRP2, OATP1A2, etc., and have shed light on their involvement in tumorigenesis, particularly in cancers such as those affecting the liver and gastrointestinal tract. While BATs' role in diseases like Alagille syndrome, biliary atresia, and cirrhosis have been extensively studied, their implications in cancer warrant further investigation. This review highlights the expression and function of BATs in cancer development and emphasizes the potential of targeting these transporters as a novel therapeutic strategy for various malignancies.
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Affiliation(s)
- Bintee Bintee
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India
| | - Ruchira Banerjee
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India; Applied Biodiversity Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India
| | - Mangala Hegde
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India
| | - Ravichandran Vishwa
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India
| | - Mohammed S Alqahtani
- Radiological Sciences Department, College of Applied Medical Sciences, King Khalid University, Abha, 61421, Saudi Arabia; BioImaging Unit, Space Research Centre, Michael Atiyah Building, University of Leicester, Leicester, LE1 7RH, United Kingdom
| | - Mohamed Abbas
- Electrical Engineering Department, College of Engineering, King Khalid University, Abha, 61421, Saudi Arabia
| | - Athba Alqahtani
- Research Centre, King Fahad Medical City, P.O. Box: 59046, Riyadh, 11525, Saudi Arabia
| | - Latha Rangan
- Applied Biodiversity Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore; NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117699, Singapore.
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, 781039, Assam, India.
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Amaral Raposo M, Sousa Oliveira E, Dos Santos A, Guadagnini D, El Mourabit H, Housset C, Lemoinne S, Abdalla Saad MJ. Impact of cholecystectomy on the gut-liver axis and metabolic disorders. Clin Res Hepatol Gastroenterol 2024; 48:102370. [PMID: 38729564 DOI: 10.1016/j.clinre.2024.102370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 04/28/2024] [Accepted: 05/05/2024] [Indexed: 05/12/2024]
Abstract
Cholecystectomy is considered as a safe procedure to treat patients with gallstones. However, epidemiological studies highlighted an association between cholecystectomy and metabolic disorders, such as type 2 diabetes mellitus and metabolic dysfunction-associated steatotic liver disease (MASLD), independently of the gallstone disease. Following cholecystectomy, bile acids flow directly from the liver into the intestine, leading to changes in the entero-hepatic circulation of bile acids and their metabolism. The changes in bile acids metabolism impact the gut microbiota. Therefore, cholecystectomized patients display gut dysbiosis characterized by a reduced diversity, a loss of bacteria producing short-chain fatty acids and an increase in pro-inflammatory bacteria. Alterations of both bile acids metabolism and gut microbiota occurring after cholecystectomy can promote the development of metabolic disorders. In this review, we discuss the impact of cholecystectomy on bile acids and gut microbiota and its consequences on metabolic functions.
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Affiliation(s)
- Mariana Amaral Raposo
- Department of Internal Medicine, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas - São Paulo, Brazil; Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA) and Institute of Cardiometabolism and Nutrition (ICAN), Paris, France
| | - Emília Sousa Oliveira
- Department of Internal Medicine, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas - São Paulo, Brazil
| | - Andrey Dos Santos
- Department of Internal Medicine, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas - São Paulo, Brazil
| | - Dioze Guadagnini
- Department of Internal Medicine, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas - São Paulo, Brazil
| | - Haquima El Mourabit
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA) and Institute of Cardiometabolism and Nutrition (ICAN), Paris, France
| | - Chantal Housset
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA) and Institute of Cardiometabolism and Nutrition (ICAN), Paris, France
| | - Sara Lemoinne
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA) and Institute of Cardiometabolism and Nutrition (ICAN), Paris, France; Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, European Reference Network on Hepatological Diseases (ERN Rare-Liver), Saint-Antoine Hospital, Assistance Publique - Hôpitaux de Paris (APHP), Paris, France.
| | - Mário José Abdalla Saad
- Department of Internal Medicine, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas - São Paulo, Brazil.
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Ceci L, Han Y, Krutsinger K, Baiocchi L, Wu N, Kundu D, Kyritsi K, Zhou T, Gaudio E, Francis H, Alpini G, Kennedy L. Gallstone and Gallbladder Disease: Biliary Tract and Cholangiopathies. Compr Physiol 2023; 13:4909-4943. [PMID: 37358507 DOI: 10.1002/cphy.c220028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/27/2023]
Abstract
Cholestatic liver diseases are named primarily due to the blockage of bile flow and buildup of bile acids in the liver. Cholestasis can occur in cholangiopathies, fatty liver diseases, and during COVID-19 infection. Most literature evaluates damage occurring to the intrahepatic biliary tree during cholestasis; however, there may be associations between liver damage and gallbladder damage. Gallbladder damage can manifest as acute or chronic inflammation, perforation, polyps, cancer, and most commonly gallstones. Considering the gallbladder is an extension of the intrahepatic biliary network, and both tissues are lined by biliary epithelial cells that share common mechanisms and properties, it is worth further evaluation to understand the association between bile duct and gallbladder damage. In this comprehensive article, we discuss background information of the biliary tree and gallbladder, from function, damage, and therapeutic approaches. We then discuss published findings that identify gallbladder disorders in various liver diseases. Lastly, we provide the clinical aspect of gallbladder disorders in liver diseases and ways to enhance diagnostic and therapeutic approaches for congruent diagnosis. © 2023 American Physiological Society. Compr Physiol 13:4909-4943, 2023.
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Affiliation(s)
- Ludovica Ceci
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Yuyan Han
- School of Biological Sciences, University of Northern Colorado, Greeley, Colorado, USA
| | - Kelsey Krutsinger
- School of Biological Sciences, University of Northern Colorado, Greeley, Colorado, USA
| | | | - Nan Wu
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Debjyoti Kundu
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Konstantina Kyritsi
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Tianhao Zhou
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Heather Francis
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Department of Research, Richard L. Roudebush VA Medical Center, Indianapolis, Indiana, USA
| | - Gianfranco Alpini
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Department of Research, Richard L. Roudebush VA Medical Center, Indianapolis, Indiana, USA
| | - Lindsey Kennedy
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Department of Research, Richard L. Roudebush VA Medical Center, Indianapolis, Indiana, USA
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Gyimesi G, Hediger MA. Transporter-Mediated Drug Delivery. Molecules 2023; 28:molecules28031151. [PMID: 36770817 PMCID: PMC9919865 DOI: 10.3390/molecules28031151] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 01/12/2023] [Accepted: 01/18/2023] [Indexed: 01/27/2023] Open
Abstract
Transmembrane transport of small organic and inorganic molecules is one of the cornerstones of cellular metabolism. Among transmembrane transporters, solute carrier (SLC) proteins form the largest, albeit very diverse, superfamily with over 400 members. It was recognized early on that xenobiotics can directly interact with SLCs and that this interaction can fundamentally determine their efficacy, including bioavailability and intertissue distribution. Apart from the well-established prodrug strategy, the chemical ligation of transporter substrates to nanoparticles of various chemical compositions has recently been used as a means to enhance their targeting and absorption. In this review, we summarize efforts in drug design exploiting interactions with specific SLC transporters to optimize their therapeutic effects. Furthermore, we describe current and future challenges as well as new directions for the advanced development of therapeutics that target SLC transporters.
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Bile Acid-Drug Interaction via Organic Anion-Transporting Polypeptide 4C1 Is a Potential Mechanism of Altered Pharmacokinetics of Renally Excreted Drugs. Int J Mol Sci 2022; 23:ijms23158508. [PMID: 35955643 PMCID: PMC9369231 DOI: 10.3390/ijms23158508] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 07/27/2022] [Accepted: 07/29/2022] [Indexed: 11/30/2022] Open
Abstract
Patients with liver diseases not only experience the adverse effects of liver-metabolized drugs, but also the unexpected adverse effects of renally excreted drugs. Bile acids alter the expression of renal drug transporters, however, the direct effects of bile acids on drug transport remain unknown. Renal drug transporter organic anion-transporting polypeptide 4C1 (OATP4C1) was reported to be inhibited by chenodeoxycholic acid. Therefore, we predicted that the inhibition of OATP4C1-mediated transport by bile acids might be a potential mechanism for the altered pharmacokinetics of renally excreted drugs. We screened 45 types of bile acids and calculated the IC50, Ki values, and bile acid−drug interaction (BDI) indices of bile acids whose inhibitory effect on OATP4C1 was >50%. From the screening results, lithocholic acid (LCA), glycine-conjugated lithocholic acid (GLCA), and taurine-conjugated lithocholic acid (TLCA) were newly identified as inhibitors of OATP4C1. Since the BDI index of LCA was 0.278, LCA is likely to inhibit OATP4C1-mediated transport in clinical settings. Our findings suggest that dose adjustment of renally excreted drugs may be required in patients with renal failure as well as in patients with hepatic failure. We believe that our findings provide essential information for drug development and safe drug treatment in clinics.
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Durník R, Šindlerová L, Babica P, Jurček O. Bile Acids Transporters of Enterohepatic Circulation for Targeted Drug Delivery. Molecules 2022; 27:molecules27092961. [PMID: 35566302 PMCID: PMC9103499 DOI: 10.3390/molecules27092961] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Revised: 04/24/2022] [Accepted: 05/02/2022] [Indexed: 12/29/2022] Open
Abstract
Bile acids (BAs) are important steroidal molecules with a rapidly growing span of applications across a variety of fields such as supramolecular chemistry, pharmacy, and biomedicine. This work provides a systematic review on their transport processes within the enterohepatic circulation and related processes. The focus is laid on the description of specific or less-specific BA transport proteins and their localization. Initially, the reader is provided with essential information about BAs′ properties, their systemic flow, metabolism, and functions. Later, the transport processes are described in detail and schematically illustrated, moving step by step from the liver via bile ducts to the gallbladder, small intestine, and colon; this description is accompanied by descriptions of major proteins known to be involved in BA transport. Spillage of BAs into systemic circulation and urine excretion are also discussed. Finally, the review also points out some of the less-studied areas of the enterohepatic circulation, which can be crucial for the development of BA-related drugs, prodrugs, and drug carrier systems.
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Affiliation(s)
- Robin Durník
- Department of Biochemistry, Faculty of Science, Masaryk University, Kamenice 5, 62500 Brno, Czech Republic;
| | - Lenka Šindlerová
- Department of Biophysics of Immune System, Institute of Biophysics, Czech Academy of Sciences, Královopolská 135, 61265 Brno, Czech Republic;
| | - Pavel Babica
- RECETOX, Faculty of Science, Masaryk University, Kotlářská 2, 61137 Brno, Czech Republic;
| | - Ondřej Jurček
- Department of Chemistry, Faculty of Science, Masaryk University, Kamenice 5, 62500 Brno, Czech Republic
- CEITEC—Central European Institute of Technology, Masaryk University, Kamenice 5, 62500 Brno, Czech Republic
- Department of Natural Drugs, Faculty of Pharmacy, Masaryk University, Palackého 1946/1, 61200 Brno, Czech Republic
- Correspondence:
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Ticho AL, Malhotra P, Dudeja PK, Gill RK, Alrefai WA. Intestinal Absorption of Bile Acids in Health and Disease. Compr Physiol 2019; 10:21-56. [PMID: 31853951 PMCID: PMC7171925 DOI: 10.1002/cphy.c190007] [Citation(s) in RCA: 134] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The intestinal reclamation of bile acids is crucial for the maintenance of their enterohepatic circulation. The majority of bile acids are actively absorbed via specific transport proteins that are highly expressed in the distal ileum. The uptake of bile acids by intestinal epithelial cells modulates the activation of cytosolic and membrane receptors such as the farnesoid X receptor (FXR) and G protein-coupled bile acid receptor 1 (GPBAR1), which has a profound effect on hepatic synthesis of bile acids as well as glucose and lipid metabolism. Extensive research has focused on delineating the processes of bile acid absorption and determining the contribution of dysregulated ileal signaling in the development of intestinal and hepatic disorders. For example, a decrease in the levels of the bile acid-induced ileal hormone FGF15/19 is implicated in bile acid-induced diarrhea (BAD). Conversely, the increase in bile acid absorption with subsequent overload of bile acids could be involved in the pathophysiology of liver and metabolic disorders such as fatty liver diseases and type 2 diabetes mellitus. This review article will attempt to provide a comprehensive overview of the mechanisms involved in the intestinal handling of bile acids, the pathological implications of disrupted intestinal bile acid homeostasis, and the potential therapeutic targets for the treatment of bile acid-related disorders. Published 2020. Compr Physiol 10:21-56, 2020.
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Affiliation(s)
- Alexander L. Ticho
- Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Pooja Malhotra
- Division of Gastroenterology & Hepatology, Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Pradeep K. Dudeja
- Division of Gastroenterology & Hepatology, Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
- jesse Brown VA Medical Center, Chicago, Illinois, USA
| | - Ravinder K. Gill
- Division of Gastroenterology & Hepatology, Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Waddah A. Alrefai
- Division of Gastroenterology & Hepatology, Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
- jesse Brown VA Medical Center, Chicago, Illinois, USA
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Ticho AL, Lee H, Gill RK, Dudeja PK, Saksena S, Lee D, Alrefai WA. A novel bioluminescence-based method to investigate uptake of bile acids in living cells. Am J Physiol Gastrointest Liver Physiol 2018; 315:G529-G537. [PMID: 29927324 PMCID: PMC6230696 DOI: 10.1152/ajpgi.00133.2018] [Citation(s) in RCA: 7] [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
Bile acid transporters, including the ileal apical sodium-dependent bile acid transporter (ASBT) and the hepatic sodium-taurocholate cotransporting polypeptide (NTCP), are crucial for the enterohepatic circulation of bile acids. Our objective was to develop a method for measuring bile acid transporter activity in real time to precisely evaluate rapid changes in their function. We designed a reporter system relying on a novel probe: cholic acid attached to luciferin via a disulfide-containing, self-immolating linker (CA-SS-Luc). Incubation of human embryonic kidney-293 cells coexpressing luciferase and ASBT with different concentrations of CA-SS-Luc (0.01-1 μM) resulted in bioluminescence with an intensity that was concentration- and time-dependent. The bioluminescence measured during incubation with 1 μM CA-SS-Luc was dependent on the levels of ASBT or NTCP expressed in the cells. Coincubation of CA-SS-Luc with natural bile acids enhanced the bioluminescence in a concentration-dependent manner with kinetic parameters for ASBT similar to those previously reported using conventional methods. These findings suggest that this method faithfully assesses ASBT function. Further, incubation with tyrosine phosphatase inhibitor III (PTPIII) led to significantly increased bioluminescence in cells expressing ASBT, consistent with previous studies showing an increase in ASBT function by PTPIII. We then investigated CA-SS-Luc in isolated mouse intestinal epithelial cells. Ileal enterocytes displayed significantly higher luminescence compared with jejunal enterocytes, indicating a transport process mediated by ileal ASBT. In conclusion, we have developed a novel method to monitor the activity of bile acid transporters in real time that has potential applications both for in vitro and in vivo studies. NEW & NOTEWORTHY This article reports the development of a real-time method for measuring the uptake of bile acids using a bioluminescent bile acid-based probe. This method has been validated for measuring uptake via the apical sodium-dependent bile acid transporter and the sodium-taurocholate cotransporting polypeptide in cell culture and ex vivo intestinal models.
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Affiliation(s)
- Alexander L. Ticho
- 3Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, Illinois
| | - Hyunjin Lee
- 4Department of Chemistry, College of Liberal Arts and Sciences, University of Illinois at Chicago, Chicago, Illinois
| | - Ravinder K. Gill
- 1Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
| | - Pradeep K. Dudeja
- 1Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois,2Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois
| | - Seema Saksena
- 1Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois,2Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois
| | - Daesung Lee
- 4Department of Chemistry, College of Liberal Arts and Sciences, University of Illinois at Chicago, Chicago, Illinois
| | - Waddah A. Alrefai
- 1Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois,2Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois
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Interactive role of diabetes mellitus and female sex in the risk of cholangiocarcinoma: A population-based nested case-control study. Oncotarget 2018; 8:6642-6651. [PMID: 28036262 PMCID: PMC5351659 DOI: 10.18632/oncotarget.14254] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Accepted: 11/30/2016] [Indexed: 12/20/2022] Open
Abstract
Diabetes mellitus (DM) has been associated with an increased risk of extrahepatic cholangiocarcinoma (ECC) and intrahepatic cholangiocarcinoma (ICC). However, the role of DM in a population with a lower incidence of ECC remains unclear. We investigated the role of DM and other risk factors for ECC and ICC by conducting a population-based, nested, case–control study in Taiwan, a region with a lower incidence but a higher proportion of ICC. We identified patients who received a diagnosis of cholangiocarcinoma (CC) from the Taiwan Cancer Registry between 2003 and 2009. A total of 6,093 CC cases (ICC: 4,695; ECC: 1,396) and 60,906 matched controls were included. Compared with the controls, the patients with ICC and ECC were more likely to have DM, with an adjusted OR of 1.22 [95% confidence interval (CI): 1.07–1.39] and 1.48 (95% CI: 1.18–1.85), respectively. DM was associated with an increased risk of CC in the women and patients without a history of biliary tract diseases. Moreover, compared with the controls, DM was not associated with an increased risk of ECC in the patients who received cholecystectomy. These findings strongly support the positive association between DM and the increased risk of both ICC and ECC; however, this association was not observed in the patients who received cholecystectomy.
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Housset C, Chrétien Y, Debray D, Chignard N. Functions of the Gallbladder. Compr Physiol 2016; 6:1549-77. [PMID: 27347902 DOI: 10.1002/cphy.c150050] [Citation(s) in RCA: 114] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The gallbladder stores and concentrates bile between meals. Gallbladder motor function is regulated by bile acids via the membrane bile acid receptor, TGR5, and by neurohormonal signals linked to digestion, for example, cholecystokinin and FGF15/19 intestinal hormones, which trigger gallbladder emptying and refilling, respectively. The cycle of gallbladder filling and emptying controls the flow of bile into the intestine and thereby the enterohepatic circulation of bile acids. The gallbladder also largely contributes to the regulation of bile composition by unique absorptive and secretory capacities. The gallbladder epithelium secretes bicarbonate and mucins, which both provide cytoprotection against bile acids. The reversal of fluid transport from absorption to secretion occurs together with bicarbonate secretion after feeding, predominantly in response to an adenosine 3',5'-cyclic monophosphate (cAMP)-dependent pathway triggered by neurohormonal factors, such as vasoactive intestinal peptide. Mucin secretion in the gallbladder is stimulated predominantly by calcium-dependent pathways that are activated by ATP present in bile, and bile acids. The gallbladder epithelium has the capacity to absorb cholesterol and provides a cholecystohepatic shunt pathway for bile acids. Changes in gallbladder motor function not only can contribute to gallstone disease, but also subserve protective functions in multiple pathological settings through the sequestration of bile acids and changes in the bile acid composition. Cholecystectomy increases the enterohepatic recirculation rates of bile acids leading to metabolic effects and an increased risk of nonalcoholic fatty liver disease, cirrhosis, and small-intestine carcinoid, independently of cholelithiasis. Among subjects with gallstones, cholecystectomy remains a priority in those at risk of gallbladder cancer, while others could benefit from gallbladder-preserving strategies. © 2016 American Physiological Society. Compr Physiol 6:1549-1577, 2016.
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Affiliation(s)
- Chantal Housset
- Sorbonne Universités, UPMC Univ Paris 06, INSERM, UMR_S 938, Centre de Recherche Saint-Antoine, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France.,Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Antoine, Centre de Référence Maladies Rares (CMR) des Maladies Inflammatoires des Voies Biliaires (MIVB), Service d'Hépatologie, Paris, France
| | - Yues Chrétien
- Sorbonne Universités, UPMC Univ Paris 06, INSERM, UMR_S 938, Centre de Recherche Saint-Antoine, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France.,Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Antoine, Centre de Référence Maladies Rares (CMR) des Maladies Inflammatoires des Voies Biliaires (MIVB), Service d'Hépatologie, Paris, France
| | - Dominique Debray
- Sorbonne Universités, UPMC Univ Paris 06, INSERM, UMR_S 938, Centre de Recherche Saint-Antoine, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France.,Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants Malades, Medical-Surgical Center, Hepatology and Transplantation, Paris, France
| | - Nicolas Chignard
- Sorbonne Universités, UPMC Univ Paris 06, INSERM, UMR_S 938, Centre de Recherche Saint-Antoine, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France
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11
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Farhat A, Crump D, Porter E, Chiu S, Letcher RJ, Su G, Kennedy SW. Time-dependent effects of the flame retardant tris(1,3-dichloro-2-propyl) phosphate (TDCPP) on mRNA expression, in vitro and in ovo, reveal optimal sampling times for rapidly metabolized compounds. ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY 2014; 33:2842-2849. [PMID: 25242413 DOI: 10.1002/etc.2755] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/09/2014] [Revised: 08/23/2014] [Accepted: 09/12/2014] [Indexed: 06/03/2023]
Abstract
The flame retardant, tris(1,3-dichloro-2-propyl) phosphate (TDCPP), was previously shown to affect chicken embryo growth, gallbladder size, and lipid homeostasis. A microarray study, however, revealed only modest transcriptional alterations in liver tissue of pipping embryos (days 20-21), which was attributed to the rapid metabolism of TDCPP throughout incubation. To identify the most appropriate sampling time for rapidly metabolized compounds, the present study assessed the time-dependent effects of TDCPP on 27 genes, in ovo (50 µg [116 nmol] TDCPP/g egg) and in vitro (10 µM), using a chicken ToxChip polymerase chain reaction array. The greatest magnitude in dysregulation (up to 362-fold) occurred on day 8 of incubation (in ovo) with alterations of genes involved in phase I, II, and III metabolism, among others. Gallbladder hypotrophy was observed by embryonic day 12, corroborating the finding in pipping embryos from our previous study. From days 12 to 19, genes involved in lipid homeostasis, steroid hormone metabolism, and oxidative stress were affected. In chicken embryonic hepatoctyes (CEHs), TDCPP was completely metabolized to bis(1,3-dichloro-2-propyl) phosphate (BDCPP) within 36 h, but transcriptional changes remained significant up to 36 h. These changes were not attributed to BDCPP exposure as it only altered 1 gene (CYP1A4). An 18-h exposure in CEHs altered the greatest number of genes, making it an appropriate time point for high-throughput chemical screening; however, depending on the biological pathways of interest, shorter or longer incubation times may be more informative. Overall, TDCPP elicits the transcriptional and phenotypic alterations observed in vitro and in ovo, whereas its major metabolite, BDCPP, is far less biologically active.
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Affiliation(s)
- Amani Farhat
- National Wildlife Research Centre, Environment Canada, Ottawa, Ontario, Canada
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Dawson PA, Karpen SJ. Intestinal transport and metabolism of bile acids. J Lipid Res 2014; 56:1085-99. [PMID: 25210150 DOI: 10.1194/jlr.r054114] [Citation(s) in RCA: 379] [Impact Index Per Article: 34.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2014] [Indexed: 12/17/2022] Open
Abstract
In addition to their classical roles as detergents to aid in the process of digestion, bile acids have been identified as important signaling molecules that function through various nuclear and G protein-coupled receptors to regulate a myriad of cellular and molecular functions across both metabolic and nonmetabolic pathways. Signaling via these pathways will vary depending on the tissue and the concentration and chemical structure of the bile acid species. Important determinants of the size and composition of the bile acid pool are their efficient enterohepatic recirculation, their host and microbial metabolism, and the homeostatic feedback mechanisms connecting hepatocytes, enterocytes, and the luminal microbiota. This review focuses on the mammalian intestine, discussing the physiology of bile acid transport, the metabolism of bile acids in the gut, and new developments in our understanding of how intestinal metabolism, particularly by the gut microbiota, affects bile acid signaling.
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Affiliation(s)
- Paul A Dawson
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Emory University, Atlanta, GA 30322
| | - Saul J Karpen
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Emory University, Atlanta, GA 30322
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Döring B, Lütteke T, Geyer J, Petzinger E. The SLC10 carrier family: transport functions and molecular structure. CURRENT TOPICS IN MEMBRANES 2013. [PMID: 23177985 DOI: 10.1016/b978-0-12-394316-3.00004-1] [Citation(s) in RCA: 98] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
The SLC10 family represents seven genes containing 1-12 exons that encode proteins in humans with sequence lengths of 348-477 amino acids. Although termed solute carriers (SLCs), only three out of seven (i.e. SLC10A1, SLC10A2, and SLC10A6) show sodium-dependent uptake of organic substrates across the cell membrane. These include the uptake of bile salts, sulfated steroids, sulfated thyroidal hormones, and certain statin drugs by SLC10A1 (Na(+)-taurocholate cotransporting polypeptide (NTCP)), the uptake of bile salts by SLC10A2 (apical sodium-dependent bile acid transporter (ASBT)), and uptake of sulfated steroids and sulfated taurolithocholate by SLC10A6 (sodium-dependent organic anion transporter (SOAT)). The other members of the family are orphan carriers not all localized in the cell membrane. The name "bile acid transporter family" arose because the first two SLC10 members (NTCP and ASBT) are carriers for bile salts that establish their enterohepatic circulation. In recent years, information has been obtained on their 2D and 3D membrane topology, structure-transport relationships, and on the ligand and sodium-binding sites. For SLC10A2, the putative 3D morphology was deduced from the crystal structure of a bacterial SLC10A2 analog, ASBT(NM). This information was used in this chapter to calculate the putative 3D structure of NTCP. This review provides first an introduction to recent knowledge about bile acid synthesis and newly found bile acid hormonal functions, and then describes step-by-step each individual member of the family in terms of expression, localization, substrate pattern, as well as protein topology with emphasis on the three functional SLC10 carrier members.
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Affiliation(s)
- Barbara Döring
- SLC10 family research group, Institute of Pharmacology and Toxicology, Justus Liebig University Giessen, Biomedical Research Center (BFS), Giessen, Germany
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Debray D, Rainteau D, Barbu V, Rouahi M, Mourabit HE, Lerondel S, Rey C, Humbert L, Wendum D, Cottart CH, Dawson P, Chignard N, Housset C. Defects in gallbladder emptying and bile Acid homeostasis in mice with cystic fibrosis transmembrane conductance regulator deficiencies. Gastroenterology 2012; 142:1581-91.e6. [PMID: 22370478 PMCID: PMC3579557 DOI: 10.1053/j.gastro.2012.02.033] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2011] [Revised: 02/06/2012] [Accepted: 02/15/2012] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Patients with cystic fibrosis (CF) have poorly defined defects in biliary function. We evaluated the effects of cystic fibrosis transmembrane conductance regulator (CFTR) deficiency on the enterohepatic disposition of bile acids (BAs). METHODS Bile secretion and BA homeostasis were investigated in Cftr(tm1Unc) (Cftr-/-) and CftrΔF508 (ΔF508) mice. RESULTS Cftr-/- and ΔF508 mice did not grow to normal size, but did not have liver abnormalities. The gallbladders of Cftr-/- mice were enlarged and had defects in emptying, based on (99m)technetium-mebrofenin scintigraphy or post-prandial variations in gallbladder volume; gallbladder contraction in response to cholecystokinin-8 was normal. Cftr-/- mice had abnormal gallbladder bile and duodenal acidity, and overexpressed the vasoactive intestinal peptide-a myorelaxant factor for the gallbladder. The BA pool was larger in Cftr-/- than wild-type mice, although there were no differences in fecal loss of BAs. Amounts of secondary BAs in portal blood, liver, and bile of Cftr-/- mice were much lower than normal. Expression of genes that are induced by BAs, including fibroblast growth factor-15 and BA transporters, was lower in the ileum but higher in the gallbladders of Cftr-/- mice, compared with wild-type mice, whereas enzymes that synthesize BA were down-regulated in livers of Cftr-/- mice. This indicates that BAs underwent a cholecystohepatic shunt, which was confirmed using cholyl-(Ne-NBD)-lysine as a tracer. In Cftr-/- mice, cholecystectomy reversed most changes in gene expression and partially restored circulating levels of secondary BAs. The ΔF508 mice overexpressed vasoactive intestinal peptide and had defects in gallbladder emptying and in levels of secondary BAs, but these features were less severe than in Cftr-/- mice. CONCLUSIONS Cftr-/- and CftrΔF508 mice have defects in gallbladder emptying that disrupt enterohepatic circulation of BAs. These defects create a shunt pathway that restricts the amount of toxic secondary BAs that enter the liver.
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Affiliation(s)
- Dominique Debray
- UPMC Univ Paris 06 and INSERM, UMR_S 938, CdR Saint-Antoine, Paris, France,AP-HP, Hôpital Necker-Enfants Malades, Hépato-Gastroentérologie Pédiatrique, Paris, France
| | - Dominique Rainteau
- UPMC Univ Paris 06 and INSERM, ERL U1057/UMR 7203, Paris, France,AP-HP, Hôpital Saint-Antoine, Biochimie, Hépato-Gastroentérologie & Anatomo-Pathologie, Paris, France
| | - Véronique Barbu
- UPMC Univ Paris 06 and INSERM, UMR_S 938, CdR Saint-Antoine, Paris, France,AP-HP, Hôpital Saint-Antoine, Biochimie, Hépato-Gastroentérologie & Anatomo-Pathologie, Paris, France
| | - Myriam Rouahi
- UPMC Univ Paris 06 and INSERM, UMR_S 938, CdR Saint-Antoine, Paris, France
| | | | | | - Colette Rey
- UPMC Univ Paris 06 and INSERM, UMR_S 938, CdR Saint-Antoine, Paris, France
| | - Lydie Humbert
- UPMC Univ Paris 06 and INSERM, ERL U1057/UMR 7203, Paris, France
| | - Dominique Wendum
- UPMC Univ Paris 06 and INSERM, UMR_S 938, CdR Saint-Antoine, Paris, France,AP-HP, Hôpital Saint-Antoine, Biochimie, Hépato-Gastroentérologie & Anatomo-Pathologie, Paris, France
| | - Charles-Henry Cottart
- UPMC Univ Paris 06 and INSERM, UMR_S 938, CdR Saint-Antoine, Paris, France,Université Paris Descartes, EA 4466, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France
| | - Paul Dawson
- Section on Gastroenterology, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina
| | - Nicolas Chignard
- UPMC Univ Paris 06 and INSERM, UMR_S 938, CdR Saint-Antoine, Paris, France
| | - Chantal Housset
- UPMC Univ Paris 06 and INSERM, UMR_S 938, CdR Saint-Antoine, Paris, France,AP-HP, Hôpital Saint-Antoine, Biochimie, Hépato-Gastroentérologie & Anatomo-Pathologie, Paris, France
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Hu NJ, Iwata S, Cameron AD, Drew D. Crystal structure of a bacterial homologue of the bile acid sodium symporter ASBT. Nature 2011; 478:408-11. [PMID: 21976025 PMCID: PMC3198845 DOI: 10.1038/nature10450] [Citation(s) in RCA: 218] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2011] [Accepted: 08/15/2011] [Indexed: 11/09/2022]
Abstract
High cholesterol levels greatly increase the risk of cardiovascular disease. By its conversion into bile acids, about 50% of cholesterol is eliminated from the body. However bile acids released from the bile duct are constantly recycled, being reabsorbed in the intestine via the Apical Sodium dependent Bile acid Transporter (ASBT). It has been shown in animal models that plasma cholesterol levels are significantly lowered by specific inhibitors of ASBT1,2, thus ASBT is a target for hypercholesterolemia drugs. Here, we describe the crystal structure of a bacterial homologue of ASBT from Neisseria meningitidis (ASBTNM) at 2.2Å. ASBTNM contains two inverted structural repeats of five transmembrane helices. A Core domain of six helices harbours two sodium ions while the remaining helices form a Panel-like domain. Overall the architecture of the protein is remarkably similar to the sodium-proton antiporter NhaA3 despite no detectable sequence homology. A bile acid molecule is situated between the Core and Panel domains in a large hydrophobic cavity. Residues near to this cavity have been shown to affect the binding of specific inhibitors of human ASBT4. The position of the bile acid together with the molecular architecture suggests the rudiments of a possible transport mechanism.
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Affiliation(s)
- Nien-Jen Hu
- Division of Molecular Biosciences, Imperial College London, London SW7 2AZ, UK
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16
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Abstract
Membrane transporters expressed by the hepatocyte and enterocyte play critical roles in maintaining the enterohepatic circulation of bile acids, an effective recycling and conservation mechanism that largely restricts these potentially cytotoxic detergents to the intestinal and hepatobiliary compartments. In doing so, the hepatic and enterocyte transport systems ensure a continuous supply of bile acids to be used repeatedly during the digestion of multiple meals throughout the day. Absorption of bile acids from the intestinal lumen and export into the portal circulation is mediated by a series of transporters expressed on the enterocyte apical and basolateral membranes. The ileal apical sodium-dependent bile acid cotransporter (abbreviated ASBT; gene symbol, SLC10A2) is responsible for the initial uptake of bile acids across the enterocyte brush border membrane. The bile acids are then efficiently shuttled across the cell and exported across the basolateral membrane by the heteromeric Organic Solute Transporter, OSTα-OSTβ. This chapter briefly reviews the tissue expression, physiology, genetics, pathophysiology, and transport properties of the ASBT and OSTα-OSTβ. In addition, the chapter discusses the relationship between the intestinal bile acid transporters and drug metabolism, including development of ASBT inhibitors as novel hypocholesterolemic or hepatoprotective agents, prodrug targeting of the ASBT to increase oral bioavailability, and involvement of the intestinal bile acid transporters in drug absorption and drug-drug interactions.
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Affiliation(s)
- Paul A Dawson
- Department of Internal Medicine, Section on Gastroenterology, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157, USA.
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Keitel V, Cupisti K, Ullmer C, Knoefel WT, Kubitz R, Häussinger D. The membrane-bound bile acid receptor TGR5 is localized in the epithelium of human gallbladders. Hepatology 2009; 50:861-70. [PMID: 19582812 DOI: 10.1002/hep.23032] [Citation(s) in RCA: 212] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
UNLABELLED TGR5 (Gpbar-1) is a plasma membrane-bound, G protein-coupled receptor for bile acids. TGR5 messenger RNA (mRNA) has been detected in many tissues, including rat cholangiocytes and mouse gallbladder. A role for TGR5 in gallstone formation has been suggested, because TGR5 knockout mice did not develop gallstones when fed a lithogenic diet. In this study, expression and localization of TGR5 was studied in human gallbladders. TGR5 mRNA and protein were detected in all 19 gallbladders. Although TGR5 mRNA was significantly elevated in the presence of gallstones, no such relation was found for TGR5 protein levels. In order to study the localization of TGR5 in human gallbladders, a novel antibody was generated. The receptor was localized in the apical membrane and the rab11-positive recycling endosome of gallbladder epithelial cells. Furthermore, the TGR5 staining colocalized with the cyclic adenosine monophosphate-regulated chloride channel cystic fibrosis transmembrane conductance regulator (CFTR) and the apical sodium-dependent bile salt uptake transporter, suggesting a functional coupling of TGR5 to bile acid uptake and chloride secretion. Stimulation with bile acids significantly increased cyclic adenosine monophosphate concentration in human gallbladder tissue. Incubation of gallbladder epithelial cells with a TGR5 agonist led to a rise of N-(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide (MQAE)-fluorescence, suggestive of a decrease in intracellular chloride concentration. The TGR5 agonist-dependent increase in MQAE-fluorescence was absent in TGR5 knockout mice or in the presence of a CFTR inhibitor, indicating that TGR5 mediates chloride secretion via activation of CFTR. The presence of the receptor in both the plasma membrane and the recycling endosome indicate that TGR5 can be regulated by translocation. CONCLUSION The data suggest a role for TGR5 in bile acid-induced fluid secretion in biliary epithelial cells.
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Affiliation(s)
- Verena Keitel
- Clinic for Gastroenterology, Hepatology and Infectiology, Heinrich-Heine-University, Düsseldorf, Germany
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Abstract
In liver and intestine, transporters play a critical role in maintaining the enterohepatic circulation and bile acid homeostasis. Over the past two decades, there has been significant progress toward identifying the individual membrane transporters and unraveling their complex regulation. In the liver, bile acids are efficiently transported across the sinusoidal membrane by the Na(+) taurocholate cotransporting polypeptide with assistance by members of the organic anion transporting polypeptide family. The bile acids are then secreted in an ATP-dependent fashion across the canalicular membrane by the bile salt export pump. Following their movement with bile into the lumen of the small intestine, bile acids are almost quantitatively reclaimed in the ileum by the apical sodium-dependent bile acid transporter. The bile acids are shuttled across the enterocyte to the basolateral membrane and effluxed into the portal circulation by the recently indentified heteromeric organic solute transporter, OSTalpha-OSTbeta. In addition to the hepatocyte and enterocyte, subgroups of these bile acid transporters are expressed by the biliary, renal, and colonic epithelium where they contribute to maintaining bile acid homeostasis and play important cytoprotective roles. This article will review our current understanding of the physiological role and regulation of these important carriers.
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Affiliation(s)
- Paul A Dawson
- Department of Internal Medicine and Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
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Abstract
In liver and intestine, transporters play a critical role in maintaining the enterohepatic circulation and bile acid homeostasis. Over the past two decades, there has been significant progress toward identifying the individual membrane transporters and unraveling their complex regulation. In the liver, bile acids are efficiently transported across the sinusoidal membrane by the Na(+) taurocholate cotransporting polypeptide with assistance by members of the organic anion transporting polypeptide family. The bile acids are then secreted in an ATP-dependent fashion across the canalicular membrane by the bile salt export pump. Following their movement with bile into the lumen of the small intestine, bile acids are almost quantitatively reclaimed in the ileum by the apical sodium-dependent bile acid transporter. The bile acids are shuttled across the enterocyte to the basolateral membrane and effluxed into the portal circulation by the recently indentified heteromeric organic solute transporter, OSTalpha-OSTbeta. In addition to the hepatocyte and enterocyte, subgroups of these bile acid transporters are expressed by the biliary, renal, and colonic epithelium where they contribute to maintaining bile acid homeostasis and play important cytoprotective roles. This article will review our current understanding of the physiological role and regulation of these important carriers.
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Affiliation(s)
- Paul A Dawson
- Department of Internal Medicine and Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
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D'Aldebert E, Biyeyeme Bi Mve MJ, Mergey M, Wendum D, Firrincieli D, Coilly A, Fouassier L, Corpechot C, Poupon R, Housset C, Chignard N. Bile salts control the antimicrobial peptide cathelicidin through nuclear receptors in the human biliary epithelium. Gastroenterology 2009; 136:1435-43. [PMID: 19245866 DOI: 10.1053/j.gastro.2008.12.040] [Citation(s) in RCA: 164] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2008] [Revised: 11/27/2008] [Accepted: 12/11/2008] [Indexed: 12/30/2022]
Abstract
BACKGROUNDS & AIMS Under normal conditions, the biliary tract is a microbial-free environment. The absence of microorganisms has been attributed to various defense mechanisms that include the physicochemical and signaling actions of bile salts. Here, we hypothesized that bile salts may stimulate the expression of a major antimicrobial peptide, cathelicidin, through nuclear receptors in the biliary epithelium. METHODS The expression of cathelicidin was analyzed in human liver samples by immunostaining and reverse-transcription quantitative polymerase chain reaction. The regulation of cathelicidin expression by the endogenous bile salt, chenodeoxycholic acid, and by the therapeutic bile salt, ursodeoxycholic acid (UDCA), was assessed in human biliary epithelial cells in which endogenous nuclear receptor expression was blunted by siRNA or dominant-negative strategies. RESULTS In the human liver, biliary epithelial cells show intense immunoreactivity for cathelicidin and for the vitamin D receptor. In cultured biliary epithelial cells, chenodeoxycholic acid and UDCA induce cathelicidin expression through 2 different nuclear receptors: the farnesoid X receptor and the vitamin D receptor, respectively. Importantly, vitamin D further increases the induction of cathelicidin expression by both bile salts. In a prototypical inflammatory biliary disease (ie, primary biliary cirrhosis), we document that hepatic expressions of the vitamin D receptor and of cathelicidin significantly increased with UDCA therapy. CONCLUSIONS Our results indicate that bile salts may contribute to biliary tract sterility by controlling epithelial cell innate immunity. They further suggest that in inflammatory biliary diseases, which involve bacterial factors, a strategy systematically combining UDCA with vitamin D would increase therapeutic efficacy.
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Affiliation(s)
- Emilie D'Aldebert
- UPMC Univ Paris 06, Inserm, UMR_S 893, CdR Saint Antoine, Paris, France
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Hardman RC, Kullman SW, Hinton DE. Non invasive in vivo investigation of hepatobiliary structure and function in STII medaka (Oryzias latipes): methodology and applications. COMPARATIVE HEPATOLOGY 2008; 7:7. [PMID: 18838008 PMCID: PMC2586619 DOI: 10.1186/1476-5926-7-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/20/2007] [Accepted: 10/06/2008] [Indexed: 01/13/2023]
Abstract
Background A novel transparent stock of medaka (Oryzias latipes; STII), recessive for all pigments found in chromatophores, permits transcutaneous imaging of internal organs and tissues in living individuals. Findings presented describe the development of methodologies for non invasive in vivo investigation in STII medaka, and the successful application of these methodologies to in vivo study of hepatobiliary structure, function, and xenobiotic response, in both 2 and 3 dimensions. Results Using brightfield, and widefield and confocal fluorescence microscopy, coupled with the in vivo application of fluorescent probes, structural and functional features of the hepatobiliary system, and xenobiotic induced toxicity, were imaged at the cellular level, with high resolution (< 1 μm), in living individuals. The findings presented demonstrate; (1) phenotypic response to xenobiotic exposure can be investigated/imaged in vivo with high resolution (< 1 μm), (2) hepatobiliary transport of solutes from blood to bile can be qualitatively and quantitatively studied/imaged in vivo, (3) hepatobiliary architecture in this lower vertebrate liver can be studied in 3 dimensions, and (4) non invasive in vivo imaging/description of hepatobiliary development in this model can be investigated. Conclusion The non-invasive in vivo methodologies described are a unique means by which to investigate biological structure, function and xenobiotic response with high resolution in STII medaka. In vivo methodologies also provide the future opportunity to integrate molecular mechanisms (e.g., genomic, proteomic) of disease and toxicity with phenotypic changes at the cellular and system levels of biological organization. While our focus has been the hepatobiliary system, other organ systems are equally amenable to in vivo study, and we consider the potential for discovery, within the context of in vivo investigation in STII medaka, as significant.
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Affiliation(s)
- Ron C Hardman
- Duke University, Environmental Sciences and Policy Division, Nicholas School of the Environment and Earth Sciences, LSRC A333, Durham, NC, USA.
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Stahl S, Davies MR, Cook DI, Graham MJ. Nuclear hormone receptor-dependent regulation of hepatic transporters and their role in the adaptive response in cholestasis. Xenobiotica 2008; 38:725-77. [DOI: 10.1080/00498250802105593] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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Portincasa P, Di Ciaula A, Wang HH, Palasciano G, van Erpecum KJ, Moschetta A, Wang DQH. Coordinate regulation of gallbladder motor function in the gut-liver axis. Hepatology 2008; 47:2112-2126. [PMID: 18506897 DOI: 10.1002/hep.22204] [Citation(s) in RCA: 91] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Gallstones are one of the most common digestive diseases with an estimated prevalence of 10%-15% in adults living in the western world, where cholesterol-enriched gallstones represent 75%-80% of all gallstones. In cholesterol gallstone disease, the gallbladder becomes the target organ of a complex metabolic disease. Indeed, a fine coordinated hepatobiliary and gastrointestinal function, including gallbladder motility in the fasting and postprandial state, is of crucial importance to prevent crystallization and precipitation of excess cholesterol in gallbladder bile. Also, gallbladder itself plays a physiopathological role in biliary lipid absorption. Here, we present a comprehensive view on the regulation of gallbladder motor function by focusing on recent discoveries in animal and human studies, and we discuss the role of the gallbladder in the pathogenesis of gallstone formation.
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Affiliation(s)
- Piero Portincasa
- Department of Internal Medicine and Public Medicine, Clinica Medica A. Murri, University of Bari Medical School, Bari, Italy.
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Hardman R, Kullman S, Yuen B, Hinton DE. Non invasive high resolution in vivo imaging of alpha-naphthylisothiocyanate (ANIT) induced hepatobiliary toxicity in STII medaka. AQUATIC TOXICOLOGY (AMSTERDAM, NETHERLANDS) 2008; 86:20-37. [PMID: 18022256 PMCID: PMC2724681 DOI: 10.1016/j.aquatox.2007.09.014] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/27/2007] [Revised: 09/13/2007] [Accepted: 09/21/2007] [Indexed: 05/25/2023]
Abstract
A novel transparent stock of medaka (Oryzias latipes; STII), homozygous recessive for all four pigments (iridophores, xanthophores, leucophores, melanophores), permits transcutaneous, high resolution (<1 microm) imaging of internal organs and tissues in living individuals. We applied this model to in vivo investigation of alpha -naphthylisothiocyanate (ANIT) induced hepatobiliary toxicity. Distinct phenotypic responses to ANIT involving all aspects of intrahepatic biliary passageways (IHBPs), particularly bile preductular epithelial cells (BPDECs), associated with transitional passageways between canaliculi and bile ductules, were observed. Alterations included: attenuation/dilation of bile canaliculi, bile preductular lesions, hydropic vacuolation of hepatocytes and BPDECs, mild BPDEC hypertrophy, and biliary epithelial cell (BEC) hyperplasia. Ex vivo histological, immunohistochemical, and ultrastructural studies were employed to aid in interpretation of, and verify, in vivo findings. 3D reconstructions from in vivo investigations provided quantitative morphometric and volumetric evaluation of ANIT exposed and untreated livers. The findings presented show for the first time in vivo evaluation of toxicity in the STII medaka hepatobiliary system, and, in conjunction with prior in vivo work characterizing normalcy, advance our comparative understanding of this lower vertebrate hepatobiliary system and its response to toxic insult.
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Affiliation(s)
- Ron Hardman
- Duke University, Nicholas School of the Environment and Earth Sciences, Durham, NC 27708, USA.
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Kanchanapoo J, Ao M, Prasad R, Moore C, Kay C, Piyachaturawat P, Rao MC. Role of protein kinase C-delta in the age-dependent secretagogue action of bile acids in mammalian colon. Am J Physiol Cell Physiol 2007; 293:C1851-61. [PMID: 17898130 DOI: 10.1152/ajpcell.00194.2007] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The role of specific PKC isoforms in the regulation of epithelial Cl(-) secretion by Ca(2+)-dependent secretagogues remains controversial. In the developing rabbit distal colon, the bile acid taurodeoxycholate (TDC) acts via intracellular calcium to stimulate Cl(-) transport in adult, but not in young, animals, whereas the PKC activator phorbol dibutyrate (PDB) stimulates Cl(-) transport at all ages. We tested the hypothesis that specific PKC isoforms account for the age-specific effects of TDC. The effects of conventional (cPKC) and novel (nPKC) PKC-specific inhibitors on TDC- and PDB-stimulated Cl(-) transport in adult and weanling colonocytes were assessed by using 6-methoxy-quinolyl acetoethyl ester. In adult colonocytes, the cPKC inhibitor Gö-6976 inhibited PDB action but not TDC action, whereas the cPKC and nPKC inhibitor Gö-6850 blocked both TDC and PDB actions. Additionally, rottlerin and the PKC-delta-specific inhibitor peptide (deltaV1-1) inhibited TDC- and PDB-stimulated Cl(-) transport in adult colonocytes. Rottlerin also decreased TDC-stimulated short-circuit current in intact colonic epithelia. Only Gö-6976, but neither rottlerin nor deltaV1-1, inhibited PDB-stimulated transport in weanling colonocytes. Colonic lysates express PKC-alpha, -lambda, and -iota protein equally at all ages, but they do not express PKC-gamma or -theta at any age. Expression of PKC-beta and PKC-epsilon protein was newborn>adult>weanling, whereas PKC-delta was expressed in adult but not in weanling or newborn colonocytes. TDC (1.6-fold) and PDB (2.0-fold) stimulated PKC-delta enzymatic activity in adult colonocytes but failed to do so in weanling colonocytes. PKC-delta mRNA expression showed age dependence. Thus PKC-delta appears critical for the action of TDC in the adult colon, and its low expression in young animals may account for their inability to secrete in response to bile acids.
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Affiliation(s)
- Jainuch Kanchanapoo
- Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand
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26
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Finzi L, Barbu V, Burgel PR, Mergey M, Kirkwood KS, Wick EC, Scoazec JY, Peschaud F, Paye F, Nadel JA, Housset C. MUC5AC, a gel-forming mucin accumulating in gallstone disease, is overproduced via an epidermal growth factor receptor pathway in the human gallbladder. THE AMERICAN JOURNAL OF PATHOLOGY 2007; 169:2031-41. [PMID: 17148666 PMCID: PMC1762466 DOI: 10.2353/ajpath.2006.060146] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Despite evidence that mucin overproduction is critical in the pathogenesis of gallstones, the mechanisms triggering mucin production in gallstone disease are unknown. Here, we tested the potential implication of an inflammation-dependent epidermal growth factor receptor (EGF-R) pathway in the regulation of gallbladder mucin synthesis. In gallbladder tissue sections from subjects with cholesterol gallstones, mucus accumulation was associated with neutrophil infiltration and with increased expressions of EGF-R and of tumor necrosis factor-alpha (TNF-alpha). In primary cultures of human gallbladder epithelial cells, TNF-alpha induced EGF-R overexpression. In the presence of TNF-alpha, EGF-R ligands (either EGF or transforming growth factor-alpha) caused significant increases in MUC5AC mRNA and protein production, whereas expression of the other gallbladder mucins MUC1, MUC3, and MUC5B was unchanged. In addition, on gallbladder tissue sections from subjects with gallstones, increased MUC5AC immunoreactivity was detected in the epithelium and within mucus gel in the lumen. Studies in primary cultures demonstrated that MUC5AC up-regulation induced by the combination of TNF-alpha with EGF-R ligands was completely blunted by inhibitors of EGF-R tyrosine kinase and mitogen-activated protein/extracellular signal-related kinase kinase. In conclusion, an inflammation-dependent EGF-R cascade causes overproduction of the gel-forming mucin MUC5AC, which accumulates in cholesterol gallstone disease. The ability to interrupt this cascade is of potential interest in the prevention of cholesterol gallstones.
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Affiliation(s)
- Laetitia Finzi
- INSERM U680, Faculté de Médecine Pierre et Marie Curie (Université Pierre et Marie Curie-Paris 6), Site Saint-Antoine, 27 rue Chaligny, 75571 Paris cedex 12, France
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27
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Swales KE, Korbonits M, Carpenter R, Walsh DT, Warner TD, Bishop-Bailey D. The Farnesoid X Receptor Is Expressed in Breast Cancer and Regulates Apoptosis and Aromatase Expression. Cancer Res 2006; 66:10120-6. [PMID: 17047076 DOI: 10.1158/0008-5472.can-06-2399] [Citation(s) in RCA: 127] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Bile acids are present at high concentrations in breast cysts and in the plasma of postmenopausal women with breast cancer. The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily that regulates bile acid homeostasis. FXR was detected in normal and tumor breast tissue, with a high level of expression in ductal epithelial cells of normal breast and infiltrating ductal carcinoma cells. FXR was also present in the human breast carcinoma cells, MCF-7 and MDA-MB-468. Activation of FXR by high concentrations of ligands induced MCF-7 and MDA-MB-468 apoptosis. At lower concentrations that had no direct effect on viability, the FXR agonist GW4064 induced expression of mRNA for the FXR target genes, small heterodimer partner (SHP), intestinal bile acid binding protein, and multidrug resistance-associated protein 2 (MRP-2), and repressed the expression of the SHP target gene aromatase. In contrast to MRP-2, mRNA for the breast cancer target genes MDR-3, MRP-1, and solute carrier transporter 7A5 were decreased. Although multidrug resistance transporters were regulated and are known FXR target genes, GW4064 had no effect on the cell death induced by the anticancer drug paclitaxel. Our findings show for the first time that FXR is expressed in breast cancer tissue and has multiple properties that could be used for the treatment of breast cancer.
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MESH Headings
- ATP Binding Cassette Transporter, Subfamily B/biosynthesis
- ATP Binding Cassette Transporter, Subfamily B/genetics
- Apoptosis/drug effects
- Apoptosis/physiology
- Aromatase/biosynthesis
- Breast Neoplasms/drug therapy
- Breast Neoplasms/genetics
- Breast Neoplasms/metabolism
- Breast Neoplasms/pathology
- Carcinoma, Ductal, Breast/enzymology
- Carcinoma, Ductal, Breast/genetics
- Carcinoma, Ductal, Breast/metabolism
- Carcinoma, Ductal, Breast/pathology
- Cell Line, Tumor
- DNA-Binding Proteins/agonists
- DNA-Binding Proteins/biosynthesis
- DNA-Binding Proteins/genetics
- Humans
- Hydroxysteroid Dehydrogenases/biosynthesis
- Hydroxysteroid Dehydrogenases/genetics
- Isoxazoles/pharmacology
- Ligands
- Multidrug Resistance-Associated Protein 2
- RNA, Messenger/biosynthesis
- RNA, Messenger/genetics
- Receptors, Cytoplasmic and Nuclear/agonists
- Receptors, Cytoplasmic and Nuclear/biosynthesis
- Receptors, Cytoplasmic and Nuclear/genetics
- Transcription Factors/agonists
- Transcription Factors/biosynthesis
- Transcription Factors/genetics
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Affiliation(s)
- Karen E Swales
- Cardiac, Vascular and Inflammation Research, William Harvey Research Institute, Charterhouse Square, London EC1M 6BQ, United Kingdom
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Neimark E, Chen F, Li X, Magid MS, Alasio TM, Frankenberg T, Sinha J, Dawson PA, Shneider BL. c-Fos is a critical mediator of inflammatory-mediated repression of the apical sodium-dependent bile acid transporter. Gastroenterology 2006; 131:554-67. [PMID: 16890608 DOI: 10.1053/j.gastro.2006.05.002] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2005] [Accepted: 04/27/2006] [Indexed: 02/03/2023]
Abstract
BACKGROUND & AIMS Ileal bile acid malabsorption is present in Crohn's ileitis. The molecular mechanisms of regulation of the apical sodium-dependent bile acid transporter (ASBT) by inflammatory cytokines in vitro and in vivo are investigated. METHODS Transient transfection studies of the human, mouse, and rat ASBT promoters and Northern analyses were performed in cells treated with the inflammatory cytokines and/or various activator protein-1 constructs. Rat ASBT promoter transgenic, wild-type, and c-fos-null mice were treated with indomethacin to assess the response to acute inflammation of the ileal mucosa. RESULTS In Caco-2 cells, ASBT messenger RNA expression was reduced 65% after interleukin-1beta treatment, while c-fos and c-jun were up-regulated 2-fold. Human ASBT promoter activity was enhanced by c-jun and repressed by a dominant negative c-jun, c-fos, or a dominant negative c-fos. Meanwhile, c-fos antisense treatment activated the human ASBT promoter 5-fold and not only abrogated interleukin-1beta-mediated repression but led to a paradoxical increase in ASBT promoter activity. Indomethacin-induced acute ileitis led to repression of ASBT in wild-type mice and in the transgenic rat ASBT promoter reporter, while paradoxical activation of ASBT was seen in c-fos-null mice. Indomethacin-induced ileal injury was greater in the c-fos-null mice compared with the wild-type littermates. CONCLUSIONS Human, rat, and mouse ASBT is inhibited by inflammatory cytokines via direct interactions of c-fos with the ASBT promoter.
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Affiliation(s)
- Ezequiel Neimark
- Division of Pediatric Hepatology, Department of Pediatrics, Mount Sinai School of Medicine, New York, New York 10029, USA
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29
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Briz O, Romero MR, Martinez-Becerra P, Macias RIR, Perez MJ, Jimenez F, San Martin FG, Marin JJG. OATP8/1B3-mediated cotransport of bile acids and glutathione: an export pathway for organic anions from hepatocytes? J Biol Chem 2006; 281:30326-35. [PMID: 16877380 DOI: 10.1074/jbc.m602048200] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
In cholestasis, the accumulation of organic anions in hepatocytes is reduced by transporters (multidrug resistance-associated proteins and OSTalpha-OSTbeta) able to extrude them across the basolateral membrane. Here we investigated whether organic anion-transporting polypeptides (OATPs) may contribute to this function. Xenopus laevis oocytes expressing human carboxylesterase-1 efficiently loaded cholic acid (CA) methyl ester, which was cleaved to CA and exported. Expression of OATP8/1B3 enhanced CA efflux, which was trans-activated by taurocholate but trans-inhibited by reduced (GSH) and oxidized (GSSG) glutathione. Moreover, taurocholate and estradiol 17beta-D-glucuronide, but not bicarbonate and glutamate, cis-inhibited OATP8/1B3-mediated bile acid transport, whereas glutathione cis-stimulated this process, which involved the transport of glutathione itself with a stoichiometry of 2:1 (GSH/bile acid). No cis-activation by glutathione of OATP-C/1B1 was found. Using real time quantitative reverse transcription-PCR, the absolute abundance of OATP-A/1A2, OATP-C/1B1, and OATP8/1B3 mRNA in human liver biopsies was measured. In healthy liver, expression levels of OATP-C/1B1 were approximately 5-fold those of OATP8/1B3 and >100-fold those of OATP-A/1A2. This situation was not substantially modified in several cholestatic liver diseases studied here. In conclusion, although both OATP-C/1B1 and OATP8/1B3 are highly expressed, and able to transport bile acids, their mechanisms of action are different. OATP-C/1B1 may be involved in uptake processes, whereas OATP8/1B3 may mediate the extrusion of organic anions by symporting with glutathione as a normal route of exporting metabolites produced by hepatocytes or preventing their intracellular accumulation when their vectorial traffic toward the bile is impaired.
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Affiliation(s)
- Oscar Briz
- Research Unit, University Hospital, Salamanca, Spain
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30
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31
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Abstract
Cholangiocytes are exposed to high concentrations of bile acids at their apical membrane. A selective transporter for bile acids, the Apical Sodium Bile Acid Cotransporter (ASBT) (also referred to as Ibat; gene name Slc10a2) is localized on the cholangiocyte apical membrane. On the basolateral membrane, four transport systems have been identified (t-ASBT, multidrug resistance (MDR)3, an unidentified anion exchanger system and organic solute transporter (Ost) heteromeric transporter, Ostα-Ostβ. Together, these transporters unidirectionally move bile acids from ductal bile to the circulation. Bile acids absorbed by cholangiocytes recycle via the peribiliary plexus back to hepatocytes for re-secretion into bile. This recycling of bile acids between hepatocytes and cholangiocytes is referred to as the cholehepatic shunt pathway. Recent studies suggest that the cholehepatic shunt pathway may contribute in overall hepatobiliary transport of bile acids and to the adaptation to chronic cholestasis due to extrahepatic obstruction. ASBT is acutely regulated by an adenosine 3', 5’-monophosphate (cAMP)-dependent translocation to the apical membrane and by phosphorylation-dependent ubiquitination and proteasome degradation. ASBT is chronically regulated by changes in gene expression in response to biliary bile acid concentration and inflammatory cytokines. Another potential function of cholangiocyte ASBT is to allow cholangiocytes to sample biliary bile acids in order to activate intracellular signaling pathways. Bile acids trigger changes in intracellular calcium, protein kinase C (PKC), phosphoinositide 3-kinase (PI3K), mitogen-activated protein (MAP) kinase and extracellular signal-regulated protein kinase (ERK) intracellular signals. Bile acids significantly alter cholangiocyte secretion, proliferation and survival. Different bile acids have differential effects on cholangiocyte intracellular signals, and in some instances trigger opposing effects on cholangiocyte secretion, proliferation and survival. Based upon these concepts and observations, the cholangiocyte has been proposed to be the principle target cell for bile acids in the liver.
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Affiliation(s)
- Xuefeng Xia
- University of Texas at Houston Medical School, 6431 Fannin Street, MSB 4.234, Houston TX 77030, USA
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Demeilliers C, Jacquemin E, Barbu V, Mergey M, Paye F, Fouassier L, Chignard N, Housset C, Lomri NE. Altered hepatobiliary gene expressions in PFIC1: ATP8B1 gene defect is associated with CFTR downregulation. Hepatology 2006; 43:1125-34. [PMID: 16628629 DOI: 10.1002/hep.21160] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Recent reports in patients with PFIC1 have indicated that a gene defect in ATP8B1 could cause deregulations in bile salt transporters through decreased expression and/or activity of FXR. This study aimed to: (1) define ATP8B1 expression in human hepatobiliary cell types, and (2) determine whether ATP8B1 defect affects gene expressions related to bile secretion in these cells. ATP8B1 expression was detected by RT-PCR in hepatocytes and cholangiocytes isolated from normal human liver and gallbladder. ATP8B1 mRNA levels were 20- and 200-fold higher in bile duct and gallbladder epithelial cells, respectively, than in hepatocytes. RT-PCR analyses of the liver from two patients with PFIC1, one with PFIC2, one with biliary atresia, showed that, compared to normal liver, hepatic expressions of FXR, SHP, CYP7A1, ASBT were decreased at least by 90% in all cholestatic disorders. In contrast, NTCP transcripts were less decreased (by < or = 30% vs. 97%) in PFIC1 as compared with other cholestatic disorders, while BSEP transcripts, in agreement with BSEP immunohistochemical signals, were normal or less decreased (by 50% vs. 97%). CFTR hepatic expression was decreased (by 80%), exclusively in PFIC1, while bile duct mass was not reduced, as ascertained by cytokeratin-19 immunolabeling. In Mz-ChA-2 human biliary epithelial cells, a significant decrease in CFTR expression was associated with ATP8B1 invalidation by siRNA. In conclusion, cholangiocytes are a major site ofATP8B1 hepatobiliary expression. A defect of ATP8B1 along with CFTR downregulation can impair the contribution of these cells to bile secretion, and potentially explain the extrahepatic cystic fibrosis-like manifestations that occur in PFIC1.
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Affiliation(s)
- Christine Demeilliers
- Université de Cergy-Pontoise, GRP2H, Département de Biologie, Errmece, Cergy-Pontoise, France
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33
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Chignard N, Mergey M, Barbu V, Finzi L, Tiret E, Paul A, Housset C. VPAC1 expression is regulated by FXR agonists in the human gallbladder epithelium. Hepatology 2005; 42:549-57. [PMID: 16037943 DOI: 10.1002/hep.20806] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/07/2022]
Abstract
Vasoactive intestinal peptide receptor-1 (VPAC1) is the high-affinity receptor of vasoactive intestinal peptide (VIP), a major regulator of bile secretion. To better define the level at which VPAC1 stimulates bile secretion, we examined its expression in the different cell types participating in bile formation (i.e., hepatocytes, bile duct, and gallbladder epithelial cells). Because VPAC1 expression was previously shown to be regulated by nuclear receptors, we tested the hypothesis that it may be regulated by the farnesoid X receptor (FXR). Quantitative RT-PCR and immunoblot analyses of cell isolates indicated that VPAC1 is expressed in all three cell types lining the human biliary tree, with predominant expression in the gallbladder. In primary cultures of human gallbladder epithelial cells, VIP induced cAMP production and chloride secretion. Analysis of the VPAC1 gene revealed the presence of potential FXR response element sequences, and both FXR and RXRalpha expressions were detected in gallbladder epithelial cells. In these cells, the FXR pharmacological agonist GW4064 upregulated VPAC1 expression in a dose-dependent manner, and this effect was antagonized by the RXRalpha ligand, 9-cis retinoic acid. Chenodeoxycholate activated endogenous FXR in gallbladder epithelial cells, as ascertained by electromobility shift assay and upregulation of the FXR target gene, small heterodimer partner. Chenodeoxycholate also provoked an increase in VPAC1 mRNA and protein content in these cells. In conclusion, FXR agonists may increase gallbladder fluid secretion through transcriptional activation of VPAC1, which may contribute to the regulation of bile secretion by bile salts and to a protective effect of FXR pharmacological agonists in gallstone disease.
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Affiliation(s)
- Nicolas Chignard
- Inserm, Paris, France, and Université Pierre et Marie Curie, Paris, France
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Pauli-Magnus C, Stieger B, Meier Y, Kullak-Ublick GA, Meier PJ. Enterohepatic transport of bile salts and genetics of cholestasis. J Hepatol 2005; 43:342-57. [PMID: 15975683 DOI: 10.1016/j.jhep.2005.03.017] [Citation(s) in RCA: 109] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2005] [Revised: 03/29/2005] [Accepted: 03/29/2005] [Indexed: 12/24/2022]
Affiliation(s)
- Christiane Pauli-Magnus
- Division of Clinical Pharmacology and Toxicology, University Hospital Zurich, Rämistrasse 100, E RAE 09, 8091 Zurich, Switzerland.
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Yuan ZB, Han TQ, Jiang ZY, Fei J, Zhang Y, Qin J, Tian ZJ, Shang J, Jiang ZH, Cai XX, Jiang Y, Zhang SD. Expression profiling suggests a regulatory role of gallbladder in lipid homeostasis. World J Gastroenterol 2005; 11:2109-16. [PMID: 15810076 PMCID: PMC4305779 DOI: 10.3748/wjg.v11.i14.2109] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To examine expression profile of gallbladder using microarray and to investigate the role of gallbladder in lipid homeostasis.
METHODS: 33P-labelled cDNA derived from total RNA of gallbladder tissue was hybridized to a cDNA array representing 17000 cDNA clusters. Genes with intensities ≥2 and variation <0.33 between two samples were considered as positive signals with subtraction of background chosen from an area where no cDNA was spotted. The average gray level of two gallbladders was adopted to analyze its bioinformatics. Identified target genes were confirmed by touch-down polymerase chain reaction and sequencing.
RESULTS: A total of 11 047 genes expressed in normal gallbladder, which was more than that predicted by another author, and the first 10 genes highly expressed (high gray level in hybridization image), e.g., ARPC5 (2225.88±90.46), LOC55972 (2220.32±446.51) and SLC20A2 (1865.21±98.02), were related to the function of smooth muscle contraction and material transport. Meanwhile, 149 lipid-related genes were expressed in the gallbladder, 89 of which were first identified (with gray level in hybridization image), e.g., FASN (11.42±2.62), APOD (92.61±8.90) and CYP21A2 (246.11±42.36), and they were involved in each step of lipid metabolism pathway. In addition, 19 of those 149 genes were gallstone candidate susceptibility genes (with gray level in hybridization image), e.g., HMGCR (10.98±0.31), NPC1 (34.88±12.12) and NR1H4 (16.8±0.65), which were previously thought to be expressed in the liver and/or intestine tissue only.
CONCLUSION: Gallbladder expresses 11 047 genes and takes part in lipid homeostasis.
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Affiliation(s)
- Zuo-Biao Yuan
- Department of Surgery, Ruijin Hospital, Shanghai Second Medical University, Shanghai 200025, China
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Abstract
The past decade has brought tremendous growth in the under-standing of the pathophysiologic mechanisms involved in cholestasis, both at the genetic and acquired levels. The discovery and characterization of an array of hepatobiliary transport proteins, the nuclear receptors that regulate them, and the potential clinical implications of these defective, altered, or variably expressed proteins are the key elements of our current understanding of cholestasis. It is hoped that future studies will enhance therapeutic options and the ability to care for patients with cholestatic disorders.
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Affiliation(s)
- Grant F Hutchins
- Division of Gastroenterology and Hepatology, 982000 University of Nebraska Medical Center, Omaha, NE 68198, USA
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Kullak-Ublick GA, Stieger B, Meier PJ. Enterohepatic bile salt transporters in normal physiology and liver disease. Gastroenterology 2004; 126:322-42. [PMID: 14699511 DOI: 10.1053/j.gastro.2003.06.005] [Citation(s) in RCA: 465] [Impact Index Per Article: 22.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The vectorial transport of bile salts from blood into bile is essential for the generation of bile flow, solubilization of cholesterol in bile, and emulsification of lipids in the intestine. Major transport proteins involved in the enterohepatic circulation of bile salts include the hepatocellular bile salt export pump (BSEP, ABCB11), the apical sodium-dependent bile salt transporter (ASBT, SLC10A2) in cholangiocytes and enterocytes, the sodium-dependent hepatocyte bile salt uptake system NTCP (SLC10A1), the organic anion transporting polypeptides OATP-C (SLC21A6), OATP8 (SLC21A8) and OATP-A (SLC21A3), and the multidrug resistance protein MRP3 (ABCC3). Synthesis and transport of bile salts are intricately linked processes that undergo extensive feedback and feed-forward regulation by transcriptional and posttranscriptional mechanisms. A key regulator of hepatocellular bile salt homeostasis is the bile acid receptor/farnesoid X receptor FXR, which activates transcription of the BSEP and OATP8 genes and of the small heterodimer partner 1 (SHP). SHP is a transcriptional repressor that mediates bile acid-induced repression of the bile salt uptake systems rat Ntcp and human OATP-C. A nuclear receptor that activates rodent Oatp2 (Slc21a5) and human MRP2 (ABCC2) is the pregnane X receptor/steroid X receptor PXR/SXR. Intracellular trafficking and membrane insertion of bile salt transporters is regulated by lipid, protein, and extracellular signal-related kinases in response to physiologic stimuli such as cyclic adenosine monophosphate or taurocholate. Finally, dysfunction of individual bile salt transporters such as BSEP, on account of genetic mutations, steric inhibition, suppression of gene expression, or disturbed signaling, is an important cause of cholestatic liver disease.
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Affiliation(s)
- Gerd A Kullak-Ublick
- Division of Clinical Pharmacology and Toxicology, Department of Internal Medicine, University Hospital, Zurich, Switzerland
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Abstract
Drug transporters are increasingly recognized as a key determinant of drug disposition. Recent studies have revealed that targeted expression of drug uptake and efflux transporters to specific cell membrane domains allows for the efficient directional movement of many drugs in clinical use. While the role of certain efflux transporters such as MDR1 (P-glycoprotein) in drug disposition has been extensively studied, emerging evidence suggests that uptake transporters may also be important to the intestinal absorption and renal or hepatic elimination of drugs. Members of the organic anion-transporting polypeptide (OATP) family of drug uptake transporters have been found capable of transporting a large array of structurally divergent drugs. Moreover, expression of OATP isoforms in the gastrointestinal tract, liver and kidney, as well as at the level of the blood-brain barrier, has important implications for our understanding of the factors governing drug absorption, elimination and tissue penetration.
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Affiliation(s)
- R B Kim
- Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
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Poupon RE, Lindor KD, Parés A, Chazouillères O, Poupon R, Heathcote EJ. Combined analysis of the effect of treatment with ursodeoxycholic acid on histologic progression in primary biliary cirrhosis. J Hepatol 2003; 39:12-6. [PMID: 12821038 DOI: 10.1016/s0168-8278(03)00192-2] [Citation(s) in RCA: 147] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND/AIMS This study aimed at evaluating the effect of ursodeoxycholic acid (UDCA) treatment on histologic progression in primary biliary cirrhosis (PBC). METHODS Using combined individual histologic findings from four clinical trials, we selected the patients in whom paired liver-biopsy specimens were available with a time interval of about 36 months between biopsies. A total of 367 patients were selected (UDCA: 200 vs. placebo: 167). RESULTS Overall, there was no significant difference in the progression of the histologic stage between the two groups. By contrast, in the subgroup of patients with initial stages I-II (n=177) there was a significant decrease in the histologic stage progression in the UDCA group relative to the placebo group (P<0.03). Overall, there was a significant delay in the progression of periportal necroinflammatory lesions (P=0.03), and an improvement in the degree of ductular proliferation (P=0.02) in the UDCA group compared with the placebo group. There was no significant difference in the progression of other specific lesions. CONCLUSIONS A 2-year UDCA treatment reduces periportal necroinflammation and improves ductular proliferation, and when initiated at the earlier stages I-II of the disease also delays the progression of histologic stage. These data support the early initiation of the drug to prevent these histologic features of PBC.
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Affiliation(s)
- Renée Eugénie Poupon
- Inserm Unit 370, Faculté de Médecine Necker, 156 rue de Vaugirard, 75730 Paris Cedex 15, France.
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40
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Xiao ZL, Biancani P, Carey MC, Behar J. Hydrophilic but not hydrophobic bile acids prevent gallbladder muscle dysfunction in acute cholecystitis. Hepatology 2003; 37:1442-50. [PMID: 12774024 DOI: 10.1053/jhep.2003.50243] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The pathogenesis of acute cholecystitis (AC) is controversial. Bile acids may be involved in the pathogenesis of AC because the hydrophobic chenodeoxycholic acid (CDCA) reproduced in vitro the muscle dysfunction observed in AC and was prevented by the hydrophilic ursodeoxycholic acid (UDCA). The present study examined the in vivo effects of UDCA or CDCA on gallbladder muscle dysfunction caused by AC. Guinea pigs were treated with placebo, UDCA, or CDCA for 2 weeks before sham operation or induction of AC by bile duct ligation (BDL) for 3 days. Pretreatment with oral UDCA prevented the defective contraction in response to agonists (acetylcholine [ACh], cholecystokinin 8 [CCK-8], and KCl) that occurs after BDL. Prostaglandin (PG) E(2)-induced contraction remained normal in the placebo and UDCA-treated groups but was impaired in the CDCA-treated group. Treatment with UDCA also prevented the expected increase in the levels of H(2)O(2), lipid peroxidation, and PGE(2) content in the placebo-treated AC group, whereas CDCA caused further increases in these oxidative stress markers. The binding capacity of PGE(2) to its receptors and the activity of catalase were reduced after treatment with CDCA. Treatment with UDCA enriched gallbladder bile acids with its conjugates and reduced the percentage of CDCA conjugates. In contrast, treatment with CDCA significantly decreased the percentage of UDCA in bile. In conclusion, oral treatment with UDCA prevents gallbladder muscle damage caused by BDL, whereas oral treatment with CDCA worsens the defective muscle contractility and the oxidative stress.
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Affiliation(s)
- Zuo-Liang Xiao
- Department of Medicine, Rhode Island Hospital and Brown University School of Medicine, Providence, RI, USA
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Trauner M, Boyer JL. Bile salt transporters: molecular characterization, function, and regulation. Physiol Rev 2003; 83:633-71. [PMID: 12663868 DOI: 10.1152/physrev.00027.2002] [Citation(s) in RCA: 691] [Impact Index Per Article: 31.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Molecular medicine has led to rapid advances in the characterization of hepatobiliary transport systems that determine the uptake and excretion of bile salts and other biliary constituents in the liver and extrahepatic tissues. The bile salt pool undergoes an enterohepatic circulation that is regulated by distinct bile salt transport proteins, including the canalicular bile salt export pump BSEP (ABCB11), the ileal Na(+)-dependent bile salt transporter ISBT (SLC10A2), and the hepatic sinusoidal Na(+)- taurocholate cotransporting polypeptide NTCP (SLC10A1). Other bile salt transporters include the organic anion transporting polypeptides OATPs (SLC21A) and the multidrug resistance-associated proteins 2 and 3 MRP2,3 (ABCC2,3). Bile salt transporters are also present in cholangiocytes, the renal proximal tubule, and the placenta. Expression of these transport proteins is regulated by both transcriptional and posttranscriptional events, with the former involving nuclear hormone receptors where bile salts function as specific ligands. During bile secretory failure (cholestasis), bile salt transport proteins undergo adaptive responses that serve to protect the liver from bile salt retention and which facilitate extrahepatic routes of bile salt excretion. This review is a comprehensive summary of current knowledge of the molecular characterization, function, and regulation of bile salt transporters in normal physiology and in cholestatic liver disease and liver regeneration.
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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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Chignard N, Mergey M, Veissière D, Poupon R, Capeau J, Parc R, Paul A, Housset C. Bile salts potentiate adenylyl cyclase activity and cAMP-regulated secretion in human gallbladder epithelium. Am J Physiol Gastrointest Liver Physiol 2003; 284:G205-12. [PMID: 12421748 DOI: 10.1152/ajpgi.00292.2002] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Fluid and ion secretion in the gallbladder is mainly triggered by the intracellular second messenger cAMP. We examined the action of bile salts on the cAMP-dependent pathway in the gallbladder epithelium. Primary cultures of human gallbladder epithelial cells were exposed to agonists of the cAMP pathway and/or to bile salts. Taurochenodeoxycholate and tauroursodeoxycholate increased forskolin-induced cAMP accumulation to a similar extent, without affecting cAMP basal levels. This potentiating effect was abrogated after PKC inhibition, whereas both taurochenodeoxycholate and tauroursodeoxycholate induced PKC-alpha and -delta translocation to cell membranes. Consistent with a PKC-mediated stimulation of cAMP production, the expression of six adenylyl cyclase isoforms, including PKC-regulated isoforms 5 and 7, was identified in human gallbladder epithelial cells. cAMP-dependent chloride secretion induced by isoproterenol, a beta-adrenergic agonist, was significantly increased by taurochenodeoxycholate and by tauroursodeoxycholate. In conclusion, endogenous and therapeutic bile salts via PKC regulation of adenylyl cyclase activity potentiate cAMP production in the human gallbladder epithelium. Through this action, bile salts may increase fluid secretion in the gallbladder after feeding.
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Affiliation(s)
- Nicolas Chignard
- Institut National de la Santé et de la Recherche Médicale, Hôpital Saint-Antoine, 75012 Paris, France
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Chen F, Ma L, Sartor RB, Li F, Xiong H, Sun AQ, Shneider B. Inflammatory-mediated repression of the rat ileal sodium-dependent bile acid transporter by c-fos nuclear translocation. Gastroenterology 2002; 123:2005-16. [PMID: 12454857 DOI: 10.1053/gast.2002.37055] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Ileal malabsorption of bile salts is observed in Crohn's ileitis. We define the transcriptional mechanisms involved in cytokine-mediated repression of the rat apical sodium-dependent bile acid transporter (ASBT). METHODS ASBT regulation was studied in IL-1beta-treated IEC-6 and Caco-2 cells and in indomethacin-treated rats. RESULTS Indomethacin-induced ileitis in Lewis rats leads to specific reductions in ileal ASBT messenger RNA and protein levels, whereas c-jun and c-fos are induced. The proinflammatory cytokines interleukin-1beta and tumor necrosis factor repress the activity of the ASBT promoter in Caco-2 and intestinal epithelial cell-6 cells. This effect is blocked by the proteasome inhibitor, MG-132, or by the phosphatidyl inositol 3-kinase inhibitor, wortmannin. Indomethacin (in vivo) or proinflammatory cytokine (in vitro) treatment leads to serine phosphorylation and nuclear translocation of c-fos. Mutation of a 5' activated protein (AP)-1 site inactivates the ASBT promoter, whereas mutation of the 3' site abrogates the proinflammatory cytokine-mediated repression. The 5' site binds a c-jun homodimer, whereas the 3' site binds a c-jun/c-fos heterodimer. c-Jun overexpression enhances ASBT promoter activity, whereas a dominant negative c-jun construct inactivates the promoter. c-Fos overexpression represses promoter activity. A 27 base pair cis-element from the 3' site in the ASBT promoter imparts cytokine-mediated down-regulation to a heterologous SV40 promoter construct. CONCLUSIONS The ASBT promoter contains 2 distinct cis AP-1 elements; the 5' element binds homodimeric c-jun and mediates basal transcription. Inflammation is associated with up-regulation, phosphorylation, and nuclear translocation of c-fos, which then represses ASBT promoter activity via binding of the 3' AP-1 element by a c-fos/c-jun heterodimer.
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Affiliation(s)
- Frank Chen
- Division of Pediatric Gastroenterology, Nutrition and Liver Diseases, Department of Pediatrics and the Immunobiology Center, Mount Sinai School of Medicine, New York, New York 10029, USA
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Abstract
The organic anion-transporting polypeptides (OATP) represent a family of proteins responsible for the membrane transport of a large number of endogenous and xenobiotic compounds with diverse chemical characteristics. OATPs are expressed in liver, kidney, brain and intestine suggesting that they may play a critical role in drug disposition. Naturally occurring polymorphisms in OATPs are currently being identified and for some, in vitro transport activities have been characterized. In this article, we review the molecular, biochemical and pharmacological aspects of known human OATPs including the presence and functional relevance of genetic polymorphisms.
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Affiliation(s)
- Rommel G Tirona
- Division of Clinical Pharmacology, Department of Medicine, 572 RRB-1, 23rd Ave @ Pierce Ave, Vanderbilt University School of Medicine, Nashville, TN 37232-6602, USA
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Lammert F, Wang DQH, Wittenburg H, Bouchard G, Hillebrandt S, Taenzler B, Carey MC, Paigen B. Lith genes control mucin accumulation, cholesterol crystallization, and gallstone formation in A/J and AKR/J inbred mice. Hepatology 2002; 36:1145-54. [PMID: 12395324 DOI: 10.1053/jhep.2002.36821] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
We recently identified 2 Lith genes that determine cholesterol gallstone formation in C57L/J inbred mice, which show a gallstone prevalence of approximately 80% on feeding 1.0% cholesterol and 0.5% cholic acid. The aim of this study was to explore if the same Lith loci contribute to the variation in gallstone susceptibility in a new experimental cross. After 12 weeks of feeding the lithogenic diet to inbred mice of strains A/J and AKR/J as well as their F(1) progeny, we used microscopy of bile to assess mucin accumulation, crystallization pathways, and stone formation. Backcross progeny (n = 225) were phenotyped and genotyped selectively for microsatellite markers spanning the genome. Quantitative trait loci (QTL) affecting gallstone phenotypes were identified by linkage analysis. Both inbred strains showed accumulation of mucin gel and cholesterol supersaturation. However, only strain AKR developed gallstones (prevalence of 20%), whereas strain A showed a stable liquid crystalline state and no stones. QTL analysis identified a gallstone locus on chromosome 17 (Lith3). A second gene locus on chromosome 15 that controls mucin accumulation harbors the mucin gene Glycam1, which was shown to be expressed in gallbladder epithelia by immunohistochemistry. Gallstone and mucin loci colocalized with potential QTLs affecting the formation of cholesterol crystals. In conclusion, QTL analysis identified specific gene loci determining mucin accumulation, cholesterol crystallization, and gallstone formation. Characterization of the pathophysiologic roles of Lith3 and the new biliary mucin gene Glycam1 might provide insights into primary defects of human cholelithiasis and lead to new therapeutic strategies for prestone intervention.
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Affiliation(s)
- Frank Lammert
- Department of Medicine III, University Hospital Aachen, Aachen University, Germany.
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Lee J, Shirk A, Oram JF, Lee SP, Kuver R. Polarized cholesterol and phospholipid efflux in cultured gall-bladder epithelial cells: evidence for an ABCA1-mediated pathway. Biochem J 2002; 364:475-84. [PMID: 12023891 PMCID: PMC1222593 DOI: 10.1042/bj20011493] [Citation(s) in RCA: 43] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Gall-bladder epithelial cells (GBEC) are exposed to high concentrations of cholesterol in bile. Whereas cholesterol absorption by GBEC is established, the fate of this absorbed cholesterol is not known. The aim of this study was to determine whether ABCA1 (ATP-binding cassette transporter A1) mediates cholesterol efflux in GBEC. Polarized canine GBEC were cultured on porous membrane filters allowing separate access to apical (AP) and basolateral (BL) compartments. After AP loading of cells with model bile and [14C]cholesterol, cholesterol efflux was measured. Cholesterol loading together with 8-bromo-cAMP treatment, which increased ABCA1 expression, led to a significant increase in cholesterol efflux with apolipoprotein A-I (apoA-I) as the acceptor. Cholesterol efflux was observed predominantly into the BL compartment. Similar results were found for phospholipid efflux. Confocal immunofluorescence microscopy showed a predominantly BL ABCA1 localization. Interestingly, apoA-I added to either the AP or the BL compartments elicited BL lipid efflux with cAMP treatment. No paracellular or transcellular passage of 125I-apoA-I occurred. Ligands for the nuclear hormone receptors liver X receptor alpha (LXRalpha) and retinoid X receptor (RXR) elicited AP and BL cholesterol efflux, suggesting the involvement of both ABCA1- and non-ABCA1-mediated pathways. In summary, BL cholesterol/phospholipid efflux consistent with an ABCA1-mediated mechanism occurs in GBEC. This efflux pathway is stimulated by cAMP and by LXRalpha/RXR ligands, and in the case of the cAMP pathway appears to involve a role for biliary apoA-I.
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Affiliation(s)
- Jin Lee
- Division of Gastroenterology, Box 356424, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195, USA
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Abstract
Further insights into the molecular regulation of bile acid transport and metabolism have provided the basis for a better understanding of the pathogenesis of cholestatic liver diseases. Novel insights into the mechanisms of action of ursodeoxycholic acid should advance our understanding of the treatment of cholestatic liver diseases. Mutations of transporter genes can cause hereditary cholestatic syndromes in both infants and adults as well as cholesterol gallstone disease. Important studies have been published on the pathogenesis, clinical features, and treatment of primary biliary cirrhosis, drug-induced cholestasis, and cholestasis of pregnancy.
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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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Abstract
New insights into the regulation of hepatobiliary transport proteins have provided the basis for a better understanding of the pathogenesis of cholestatic liver diseases. Mutations of transporter genes can cause hereditary cholestatic syndromes, the study of which has shed much light on the basic mechanisms of bile secretion and cholestasis. Important new studies have been published about the pathogenesis, clinical features, and treatment of primary biliary cirrhosis, primary sclerosing cholangitis, cholestasis of pregnancy, total parenteral nutrition-induced cholestasis, and drug-induced cholestasis.
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Affiliation(s)
- M Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Karl Franzens University School of Medicine, Graz, Austria
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