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Piñar-Gutiérrez A, Quintana-Gallego E, Remón-Ruiz PJ, Pizarro Á, González-Navarro I, Jiménez-Sánchez A, García-Rey S, Roque-Cuéllar MDC, Gato S, Domínguez I, Castell FJ, Romero-Gómez M, García-Luna PP. Non-invasive evaluation of steatosis and fibrosis in the liver in adults patients living with cystic fibrosis. J Cyst Fibros 2025:S1569-1993(25)00060-8. [PMID: 39956714 DOI: 10.1016/j.jcf.2025.02.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2024] [Revised: 02/06/2025] [Accepted: 02/10/2025] [Indexed: 02/18/2025]
Abstract
BACKGROUND & AIMS Cystic fibrosis hepatobiliary involvement is a heterogeneous and systemic entity. The primary objective was to determine the prevalence of steatosis, by magnetic resonance-proton density fat fraction (MR-PDFF), and liver fibrosis, by magnetic resonance elastography (MRE), in a cohort of adults with cystic fibrosis. The secondary objective was to determine the diagnostic yield of widely available non-invasive liver markers for steatosis and fibrosis, and vibration controlled transitional elastography (VCTE) releasing Control Attenuation Parameter (CAP) (dB/m) and stiffness (kPa), with the aim of proposing a diagnostic algorithm. METHODS We conducted a cross-sectional study including 101 adult patients with cystic fibrosis seen in a multidisciplinary unit. The study encompassed a clinical evaluation, morpho-functional assessment, VCTE, non-invasive liver markers and MR-PDFF and MRE. Diagnostic accuracy was assessed using ROC curves and 2 × 2 tables. RESULTS MR-PDFF detected hepatic steatosis in 18 of 101 (17.8 %) patients, while MRE detected significant liver fibrosis in 15 of 101 (14.9 %). The VCTE cut-off with the best diagnostic yield, determined by the Youden index, was 222 dB/m for the presence of steatosis (AUC 0.864 (95 % CI 0.768-0.961; p < 0.001) and the VCTE cut-off was 6.65 kPa for liver fibrosis (AUC 0.951(95 % CI 0.81-1; p = 0.053). A screening algorithm for hepatic steatosis was developed using the fatty liver index (FLI) and CAP, with a negative predictive value of 83.3 %. For liver fibrosis, it was outperformed by the Hepamet Fibrosis Score (HFS) and VCTE, with a negative predictive value of 100 %. CONCLUSIONS The prevalence of hepatic steatosis and liver fibrosis was 17.8 % and 14.9 %, respectively. VCTE alone or in combination with FLI for steatosis or HFS for fibrosis demonstrated high diagnostic accuracy. This approach effectively allows for the exclusion of steatosis and fibrosis, thereby reducing the need for MR-PDFF and MRE studies.
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Affiliation(s)
- Ana Piñar-Gutiérrez
- UGC Endocrinología y Nutrición, Hospital Universitario Virgen del Rocío, Sevilla, Spain
| | | | - Pablo J Remón-Ruiz
- UGC Endocrinología y Nutrición, Hospital Universitario Virgen del Rocío, Sevilla, Spain
| | - Ángeles Pizarro
- UGC Aparato Digestivo, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (HUVR/CSIC/US), CIBEREHD, Universidad de Sevilla, Sevilla, Spain
| | | | | | - Silvia García-Rey
- UGC Endocrinología y Nutrición, Hospital Universitario Virgen del Rocío, Sevilla, Spain
| | | | - Sheila Gato
- UGC Aparato Digestivo, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (HUVR/CSIC/US), CIBEREHD, Universidad de Sevilla, Sevilla, Spain
| | | | | | - Manuel Romero-Gómez
- UGC Aparato Digestivo, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (HUVR/CSIC/US), CIBEREHD, Universidad de Sevilla, Sevilla, Spain.
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2
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Drzymała-Czyż S, Walkowiak J, Colombo C, Alicandro G, Storrösten OT, Kolsgaard M, Bakkeheim E, Strandvik B. Fatty acid abnormalities in cystic fibrosis-the missing link for a cure? iScience 2024; 27:111153. [PMID: 39620135 PMCID: PMC11607544 DOI: 10.1016/j.isci.2024.111153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2025] Open
Abstract
The care for cystic fibrosis (CF) has dramatically changed with the development of modulators, correctors, and potentiators of the CFTR molecule, which lead to improved clinical status of most people with CF (pwCF). The modulators influence phospholipids and ceramides, but not linoleic acid (LA) deficiency, associated with more severe phenotypes of CF. The LA deficiency is associated with upregulation of its transfer to arachidonic acid (AA). The AA release from membranes is increased and associated with increase of pro-inflammatory prostanoids and the characteristic inflammation is present before birth and bacterial infections. Docosahexaenoic acid is often decreased, especially in associated liver disease Some endogenously synthesized fatty acids are increased. Cholesterol and ceramide metabolisms are disturbed. The lipid abnormalities are present at birth, and before feeding in transgenic pigs and ferrets. This review focus on the lipid abnormalities and their associations to clinical symptoms in CF, based on clinical studies and experimental research.
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Affiliation(s)
| | - Jarosław Walkowiak
- Department of Pediatric Gastroenterology and Metabolic Diseases, Institute of Pediatrics, Poznan University of Medical Sciences, Poznan, Poland
| | - Carla Colombo
- Cystic Fibrosis Centre, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, and Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Gianfranco Alicandro
- Cystic Fibrosis Centre, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, and Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Olav Trond Storrösten
- National Resource Centre for Cystic Fibrosis, Oslo University Hospital, Oslo, Norway
| | - Magnhild Kolsgaard
- National Resource Centre for Cystic Fibrosis, Oslo University Hospital, Oslo, Norway
| | - Egil Bakkeheim
- National Resource Centre for Cystic Fibrosis, Oslo University Hospital, Oslo, Norway
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3
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Gao X, Yeh HI, Yang Z, Fan C, Jiang F, Howard RJ, Lindahl E, Kappes JC, Hwang TC. Allosteric inhibition of CFTR gating by CFTRinh-172 binding in the pore. Nat Commun 2024; 15:6668. [PMID: 39107303 PMCID: PMC11303713 DOI: 10.1038/s41467-024-50641-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Accepted: 07/09/2024] [Indexed: 08/10/2024] Open
Abstract
Loss-of-function mutations of the CFTR gene cause the life-shortening genetic disease cystic fibrosis (CF), whereas overactivity of CFTR may lead to secretory diarrhea and polycystic kidney disease. While effective drugs targeting the CFTR protein have been developed for the treatment of CF, little progress has been made for diseases caused by hyper-activated CFTR. Here, we solve the cryo-EM structure of CFTR in complex with CFTRinh-172 (Inh-172), a CFTR gating inhibitor with promising potency and efficacy. We find that Inh-172 binds inside the pore of CFTR, interacting with amino acid residues from transmembrane segments (TMs) 1, 6, 8, 9, and 12 through mostly hydrophobic interactions and a salt bridge. Substitution of these residues lowers the apparent affinity of Inh-172. The inhibitor-bound structure reveals re-orientations of the extracellular segment of TMs 1, 8, and 12, supporting an allosteric modulation mechanism involving post-binding conformational changes. This allosteric inhibitory mechanism readily explains our observations that pig CFTR, which preserves all the amino acid residues involved in Inh-172 binding, exhibits a much-reduced sensitivity to Inh-172 and that the apparent affinity of Inh-172 is altered by the CF drug ivacaftor (i.e., VX-770) which enhances CFTR's activity through binding to a site also comprising TM8.
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Affiliation(s)
- Xiaolong Gao
- Dalton Cardiovascular Research Center, University of Missouri-Columbia, Columbia, MO, 65211, USA.
| | - Han-I Yeh
- Dalton Cardiovascular Research Center, University of Missouri-Columbia, Columbia, MO, 65211, USA
- Institute of Pharmacology, National Yang Ming Chiao Tung University, College of Medicine, Taipei, Taiwan
- Membrane Protein Structural Biology Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Zhengrong Yang
- Heersink School of Medicine, University of Alabama School of Medicine, Birmingham, AL, 35233, USA
| | - Chen Fan
- Department of Applied Physics, Science for Life Laboratory, KTH Royal Institute of Technology, Solna, Sweden
- Department of Biochemistry and Biophysics, Science for Life Laboratory, Stockholm University, Solna, Sweden
| | - Fan Jiang
- Heersink School of Medicine, University of Alabama School of Medicine, Birmingham, AL, 35233, USA
| | - Rebecca J Howard
- Department of Applied Physics, Science for Life Laboratory, KTH Royal Institute of Technology, Solna, Sweden
- Department of Biochemistry and Biophysics, Science for Life Laboratory, Stockholm University, Solna, Sweden
| | - Erik Lindahl
- Department of Applied Physics, Science for Life Laboratory, KTH Royal Institute of Technology, Solna, Sweden
- Department of Biochemistry and Biophysics, Science for Life Laboratory, Stockholm University, Solna, Sweden
| | - John C Kappes
- Heersink School of Medicine, University of Alabama School of Medicine, Birmingham, AL, 35233, USA
- Research Service, Birmingham Veterans Affairs Medical Center, Veterans Health Administration, Birmingham, AL, 35233, USA
| | - Tzyh-Chang Hwang
- Dalton Cardiovascular Research Center, University of Missouri-Columbia, Columbia, MO, 65211, USA.
- Institute of Pharmacology, National Yang Ming Chiao Tung University, College of Medicine, Taipei, Taiwan.
- Membrane Protein Structural Biology Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan.
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4
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Quaglia A, Roberts EA, Torbenson M. Developmental and Inherited Liver Disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:122-294. [DOI: 10.1016/b978-0-7020-8228-3.00003-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Parisi GF, Papale M, Pecora G, Rotolo N, Manti S, Russo G, Leonardi S. Cystic Fibrosis and Cancer: Unraveling the Complex Role of CFTR Gene in Cancer Susceptibility. Cancers (Basel) 2023; 15:4244. [PMID: 37686519 PMCID: PMC10486401 DOI: 10.3390/cancers15174244] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 08/06/2023] [Accepted: 08/22/2023] [Indexed: 09/10/2023] Open
Abstract
Cystic fibrosis (CF) is a genetic disorder affecting multiple organs, primarily the lungs and digestive system. Over the years, advancements in medical care and treatments have significantly increased the life expectancy of individuals with CF. However, with this improved longevity, concerns about the potential risk of developing certain types of cancers have arisen. This narrative review aims to explore the relationship between CF, increased life expectancy, and the associated risk for cancers. We discuss the potential mechanisms underlying this risk, including chronic inflammation, immune system dysregulation, and genetic factors. Additionally, we review studies that have examined the incidence and types of cancers seen in CF patients, with a focus on gastrointestinal, breast, and respiratory malignancies. We also explore the impact of CFTR modulator therapies on cancer risk. In the gastrointestinal tract, CF patients have an elevated risk of developing colorectal cancer, pancreatic cancer, and possibly esophageal cancer. The underlying mechanisms contributing to these increased risks are not fully understood, but chronic inflammation, altered gut microbiota, and genetic factors are believed to play a role. Regular surveillance and colonoscopies are recommended for early detection and management of colorectal cancer in CF patients. Understanding the factors contributing to cancer development in CF patients is crucial for implementing appropriate surveillance strategies and improving long-term outcomes. Further research is needed to elucidate the molecular mechanisms involved and develop targeted interventions to mitigate cancer risk in individuals with CF.
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Affiliation(s)
- Giuseppe Fabio Parisi
- Pediatric Respiratory Unit, Department of Clinical and Experimental Medicine, San Marco Hospital, University of Catania, Viale Carlo Azeglio Ciampi sn, 95121 Catania, Italy; (M.P.); (G.P.); (N.R.); (S.L.)
| | - Maria Papale
- Pediatric Respiratory Unit, Department of Clinical and Experimental Medicine, San Marco Hospital, University of Catania, Viale Carlo Azeglio Ciampi sn, 95121 Catania, Italy; (M.P.); (G.P.); (N.R.); (S.L.)
| | - Giulia Pecora
- Pediatric Respiratory Unit, Department of Clinical and Experimental Medicine, San Marco Hospital, University of Catania, Viale Carlo Azeglio Ciampi sn, 95121 Catania, Italy; (M.P.); (G.P.); (N.R.); (S.L.)
| | - Novella Rotolo
- Pediatric Respiratory Unit, Department of Clinical and Experimental Medicine, San Marco Hospital, University of Catania, Viale Carlo Azeglio Ciampi sn, 95121 Catania, Italy; (M.P.); (G.P.); (N.R.); (S.L.)
| | - Sara Manti
- Pediatric Unit, Department of Human and Pediatric Pathology “Gaetano Barresi”, AOUP G. Martino, University of Messina, Via Consolare Valeria, 1, 98124 Messina, Italy;
| | - Giovanna Russo
- Pediatric Hematology and Oncology Unit, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy;
| | - Salvatore Leonardi
- Pediatric Respiratory Unit, Department of Clinical and Experimental Medicine, San Marco Hospital, University of Catania, Viale Carlo Azeglio Ciampi sn, 95121 Catania, Italy; (M.P.); (G.P.); (N.R.); (S.L.)
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Wu Q, Liang X, Hou X, Song Z, Bouhamdan M, Qiu Y, Koike Y, Rajagopalan C, Wei HG, Jiang H, Hish G, Zhang J, Chen YE, Jin JP, Xu J, Zhang K, Sun F. Cystic fibrosis rabbits develop spontaneous hepatobiliary lesions and CF-associated liver disease (CFLD)-like phenotypes. PNAS NEXUS 2023; 2:pgac306. [PMID: 36712930 PMCID: PMC9832953 DOI: 10.1093/pnasnexus/pgac306] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 12/22/2022] [Indexed: 12/25/2022]
Abstract
Cystic fibrosis (CF) is an autosomal recessive genetic disease affecting multiple organs. Approximately 30% CF patients develop CF-related liver disease (CFLD), which is the third most common cause of morbidity and mortality of CF. CFLD is progressive, and many of the severe forms eventually need liver transplantation. The mechanistic studies and therapeutic interventions to CFLD are unfortunately very limited. Utilizing the CRISPR/Cas9 technology, we recently generated CF rabbits by introducing mutations to the rabbit CF transmembrane conductance regulator (CFTR) gene. Here we report the liver phenotypes and mechanistic insights into the liver pathogenesis in these animals. CF rabbits develop spontaneous hepatobiliary lesions and abnormal biliary secretion accompanied with altered bile acid profiles. They exhibit nonalcoholic steatohepatitis (NASH)-like phenotypes, characterized by hepatic inflammation, steatosis, and fibrosis, as well as altered lipid profiles and diminished glycogen storage. Mechanistically, our data reveal that multiple stress-induced metabolic regulators involved in hepatic lipid homeostasis were up-regulated in the livers of CF-rabbits, and that endoplasmic reticulum (ER) stress response mediated through IRE1α-XBP1 axis as well as NF-κB- and JNK-mediated inflammatory responses prevail in CF rabbit livers. These findings show that CF rabbits manifest many CFLD-like phenotypes and suggest targeting hepatic ER stress and inflammatory pathways for potential CFLD treatment.
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Affiliation(s)
- Qingtian Wu
- Department of Physiology, Wayne State University School of Medicine, Detroit, MI 48201, USA
| | - Xiubin Liang
- Center for Advanced Models for Translational Sciences and Therapeutics, University of Michigan Medical Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Xia Hou
- Department of Physiology, Wayne State University School of Medicine, Detroit, MI 48201, USA
| | - Zhenfeng Song
- Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA
| | - Mohamad Bouhamdan
- Department of Physiology, Wayne State University School of Medicine, Detroit, MI 48201, USA
| | - Yining Qiu
- Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA
| | - Yui Koike
- Center for Advanced Models for Translational Sciences and Therapeutics, University of Michigan Medical Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Carthic Rajagopalan
- Department of Physiology, Wayne State University School of Medicine, Detroit, MI 48201, USA
| | - Hong-Guang Wei
- Department of Physiology, Wayne State University School of Medicine, Detroit, MI 48201, USA
| | - Hong Jiang
- Department of Physiology, Wayne State University School of Medicine, Detroit, MI 48201, USA
| | - Gerry Hish
- Laboratory Animal Resources, Wayne State University School of Medicine, Detroit, MI 48201, USA
| | - Jifeng Zhang
- Center for Advanced Models for Translational Sciences and Therapeutics, University of Michigan Medical Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Y Eugene Chen
- Center for Advanced Models for Translational Sciences and Therapeutics, University of Michigan Medical Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Jian-Ping Jin
- Department of Physiology, Wayne State University School of Medicine, Detroit, MI 48201, USA
| | - Jie Xu
- Center for Advanced Models for Translational Sciences and Therapeutics, University of Michigan Medical Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Kezhong Zhang
- Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA
| | - Fei Sun
- Department of Physiology, Wayne State University School of Medicine, Detroit, MI 48201, USA
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7
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Scott J, Jones AM, Piper Hanley K, Athwal VS. Review article: epidemiology, pathogenesis and management of liver disease in adults with cystic fibrosis. Aliment Pharmacol Ther 2022; 55:389-400. [PMID: 35048397 DOI: 10.1111/apt.16749] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 10/18/2021] [Accepted: 12/13/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND Cystic fibrosis-related liver disease (CFLD) is the leading cause of death in cystic fibrosis (CF), after pulmonary disease. To improve identification and management of this condition requires an understanding of the underlying disease mechanism. AIMS This review summarises the current understanding of CFLD epidemiology, pathology, diagnosis and management. METHODS Relevant reports on cystic fibrosis liver disease were identified using a literature search and summarised. RESULTS CFLD is a heterogeneous condition with several different co-existent pathologies, including environmental and genetic factors. Incidence of clinically significant CFLD continues at a linear rate into early adulthood and has been described in up to 25% of CF patients. Diagnosis strategies lack precision and patient risk stratification needs to look beyond Childs-Pugh scoring. Efficacious therapies are lacking and, at present, newer modulator therapies lack data in CFLD and carry an increased risk of hepatotoxicity. Outcomes of liver transplant are comparable to non-CF transplant indications. CONCLUSIONS The incidence of CFLD increases with age and hence is increasingly important to adult patients with CF. Effective therapies are lacking. For progress to be made a better understanding of pathogenesis and disease detection are required.
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Affiliation(s)
- Jennifer Scott
- Division of Gastroenterology and Hepatology, Manchester University NHS Foundation Trust, Manchester, UK
- Faculty of Biology Medicine and Health, The University of Manchester, Manchester, UK
| | - Andrew M Jones
- Faculty of Biology Medicine and Health, The University of Manchester, Manchester, UK
- Manchester Adult Cystic Fibrosis Centre, Manchester University NHS Foundation Trust UK, Manchester, UK
| | - Karen Piper Hanley
- Division of Gastroenterology and Hepatology, Manchester University NHS Foundation Trust, Manchester, UK
- Faculty of Biology Medicine and Health, The University of Manchester, Manchester, UK
| | - Varinder S Athwal
- Division of Gastroenterology and Hepatology, Manchester University NHS Foundation Trust, Manchester, UK
- Faculty of Biology Medicine and Health, The University of Manchester, Manchester, UK
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8
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Kroll T, Prescher M, Smits SHJ, Schmitt L. Structure and Function of Hepatobiliary ATP Binding Cassette Transporters. Chem Rev 2020; 121:5240-5288. [PMID: 33201677 DOI: 10.1021/acs.chemrev.0c00659] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The liver is beyond any doubt the most important metabolic organ of the human body. This function requires an intensive crosstalk within liver cellular structures, but also with other organs. Membrane transport proteins are therefore of upmost importance as they represent the sensors and mediators that shuttle signals from outside to the inside of liver cells and/or vice versa. In this review, we summarize the known literature of liver transport proteins with a clear emphasis on functional and structural information on ATP binding cassette (ABC) transporters, which are expressed in the human liver. These primary active membrane transporters form one of the largest families of membrane proteins. In the liver, they play an essential role in for example bile formation or xenobiotic export. Our review provides a state of the art and comprehensive summary of the current knowledge of hepatobiliary ABC transporters. Clearly, our knowledge has improved with a breath-taking speed over the last few years and will expand further. Thus, this review will provide the status quo and will lay the foundation for new and exciting avenues in liver membrane transporter research.
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Affiliation(s)
- Tim Kroll
- Institute of Biochemistry, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany
| | - Martin Prescher
- Institute of Biochemistry, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany
| | - Sander H J Smits
- Institute of Biochemistry, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany.,Center for Structural Studies, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany
| | - Lutz Schmitt
- Institute of Biochemistry, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany
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9
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Staufer K. Current Treatment Options for Cystic Fibrosis-Related Liver Disease. Int J Mol Sci 2020; 21:E8586. [PMID: 33202578 PMCID: PMC7696864 DOI: 10.3390/ijms21228586] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Revised: 11/08/2020] [Accepted: 11/11/2020] [Indexed: 02/07/2023] Open
Abstract
Cystic Fibrosis-related liver disease (CFLD) has become a leading cause of morbidity and mortality in patients with Cystic Fibrosis (CF), and affects children and adults. The understanding of the pathogenesis of CFLD is key in order to develop efficacious treatments. However, it remains complex, and has not been clarified to the last. The search for a drug might be additionally complicated due to the diverse clinical picture and lack of a unified definition of CFLD. Although ursodeoxycholic acid has been used for decades, its efficacy in CFLD is controversial, and the potential of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulators and targeted gene therapy in CFLD needs to be defined in the near future. This review focuses on the current knowledge on treatment strategies for CFLD based on pathomechanistic viewpoints.
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Affiliation(s)
- Katharina Staufer
- Department of Visceral Surgery and Medicine, Inselspital, University Hospital Bern, 3010 Bern, Switzerland; ; Tel.: +41-31-63-2-74-88
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10
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Fabris L, Fiorotto R, Spirli C, Cadamuro M, Mariotti V, Perugorria MJ, Banales JM, Strazzabosco M. Pathobiology of inherited biliary diseases: a roadmap to understand acquired liver diseases. Nat Rev Gastroenterol Hepatol 2019; 16:497-511. [PMID: 31165788 PMCID: PMC6661007 DOI: 10.1038/s41575-019-0156-4] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Bile duct epithelial cells, also known as cholangiocytes, regulate the composition of bile and its flow. Acquired, congenital and genetic dysfunctions in these cells give rise to a set of diverse and complex diseases, often of unknown aetiology, called cholangiopathies. New knowledge has been steadily acquired about genetic and congenital cholangiopathies, and this has led to a better understanding of the mechanisms of acquired cholangiopathies. This Review focuses on findings from studies on Alagille syndrome, polycystic liver diseases, fibropolycystic liver diseases (Caroli disease and congenital hepatic fibrosis) and cystic fibrosis-related liver disease. In particular, knowledge on the role of Notch signalling in biliary repair and tubulogenesis has been advanced by work on Alagille syndrome, and investigations in polycystic liver diseases have highlighted the role of primary cilia in biliary pathophysiology and the concept of biliary angiogenic signalling and its role in cyst growth and biliary repair. In fibropolycystic liver disease, research has shown that loss of fibrocystin generates a signalling cascade that increases β-catenin signalling, activates the NOD-, LRR- and pyrin domain-containing 3 inflammasome, and promotes production of IL-1β and other chemokines that attract macrophages and orchestrate the process of pericystic and portal fibrosis, which are the main mechanisms of progression in cholangiopathies. In cystic fibrosis-related liver disease, lack of cystic fibrosis transmembrane conductance regulator increases the sensitivity of epithelial Toll-like receptor 4 that sustains the secretion of nuclear factor-κB-dependent cytokines and peribiliary inflammation in response to gut-derived products, providing a model for primary sclerosing cholangitis. These signalling mechanisms may be targeted therapeutically and they offer a possibility for the development of novel treatments for acquired cholangiopathies.
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Affiliation(s)
- Luca Fabris
- Liver Center, Department of Medicine, Yale University, New Haven, CT, USA
- Department of Molecular Medicine, University of Padova, Padova, Italy
| | - Romina Fiorotto
- Liver Center, Department of Medicine, Yale University, New Haven, CT, USA
| | - Carlo Spirli
- Liver Center, Department of Medicine, Yale University, New Haven, CT, USA
| | | | - Valeria Mariotti
- Department of Molecular Medicine, University of Padova, Padova, Italy
| | - Maria J Perugorria
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), Madrid, Spain
- IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
| | - Jesus M Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
- National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), Madrid, Spain
- IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
| | - Mario Strazzabosco
- Liver Center, Department of Medicine, Yale University, New Haven, CT, USA.
- Department of Molecular Medicine, University of Padova, Padova, Italy.
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11
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Fiorotto R, Amenduni M, Mariotti V, Cadamuro M, Fabris L, Spirli C, Strazzabosco M. Animal models for cystic fibrosis liver disease (CFLD). Biochim Biophys Acta Mol Basis Dis 2018; 1865:965-969. [PMID: 30071276 DOI: 10.1016/j.bbadis.2018.07.026] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Revised: 07/18/2018] [Accepted: 07/19/2018] [Indexed: 12/20/2022]
Abstract
Liver disease is a severe complication in patients with Cystic Fibrosis (CF), a genetic disease caused by mutations in the gene encoding for cystic fibrosis transmembrane conductance regulator (CFTR) channel. The sequence of events leading to CFLD is still unclear and has limited the development of more specific treatments other than the bile acid UDCA. However, in the last twenty years, several gaps have been filled, which have mainly been possible due to the availability of different animal models that mimic CF. CF mice, although they lack a spontaneous liver manifestation, have been essential to better understand the multiple functions of CFTR expression on the apical membrane of cholangiocytes, from chloride channel to regulator of epithelial innate immunity. Additionally, we have learned that the gut microbiota might be a pathogenetic factor for the development of liver disease. The recent creation of novel CF animal models (i.e. pig and ferret) that better reproduce the human disease, will allow for comparative studies with species that spontaneously develop the liver disease and will hopefully lead to novel therapeutic treatments. In this review, we have compared and summarized the main features of the current available CF animal models and their applicability for the study of the liver phenotype.
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Affiliation(s)
- Romina Fiorotto
- Digestive Disease Section, Yale Liver Center, Yale University School of Medicine, New Haven, CT, USA
| | - Mariangela Amenduni
- Digestive Disease Section, Yale Liver Center, Yale University School of Medicine, New Haven, CT, USA
| | - Valeria Mariotti
- Department of Molecular Medicine, University of Padova School of Medicine, Padova, Italy
| | - Massimiliano Cadamuro
- Department of Molecular Medicine, University of Padova School of Medicine, Padova, Italy
| | - Luca Fabris
- Department of Molecular Medicine, University of Padova School of Medicine, Padova, Italy
| | - Carlo Spirli
- Digestive Disease Section, Yale Liver Center, Yale University School of Medicine, New Haven, CT, USA.
| | - Mario Strazzabosco
- Digestive Disease Section, Yale Liver Center, Yale University School of Medicine, New Haven, CT, USA
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Fiorotto R, Amenduni M, Mariotti V, Fabris L, Spirli C, Strazzabosco M. Src kinase inhibition reduces inflammatory and cytoskeletal changes in ΔF508 human cholangiocytes and improves cystic fibrosis transmembrane conductance regulator correctors efficacy. Hepatology 2018; 67:972-988. [PMID: 28836688 PMCID: PMC5783790 DOI: 10.1002/hep.29400] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2017] [Revised: 07/18/2017] [Accepted: 07/20/2017] [Indexed: 12/15/2022]
Abstract
Cystic fibrosis transmembrane conductance regulator (CFTR), the channel mutated in cystic fibrosis (CF), is expressed by the biliary epithelium (i.e., cholangiocytes) of the liver. Progressive clinical liver disease (CF-associated liver disease; CFLD) occurs in around 10% of CF patients and represents the third leading cause of death. Impaired secretion and inflammation contribute to CFLD; however, the lack of human-derived experimental models has hampered the understanding of CFLD pathophysiology and the search for a cure. We have investigated the cellular mechanisms altered in human CF cholangiocytes using induced pluripotent stem cells (iPSCs) derived from healthy controls and a ΔF508 CFTR patient. We have devised a novel protocol for the differentiation of human iPSC into polarized monolayers of cholangiocytes. Our results show that iPSC-cholangiocytes reproduced the polarity and the secretory function of the biliary epithelium. Protein kinase A/cAMP-mediated fluid secretion was impaired in ΔF508 cholangiocytes and negligibly improved by VX-770 and VX-809, two small molecule drugs used to correct and potentiate ΔF508 CFTR. Moreover, ΔF508 cholangiocytes showed increased phosphorylation of Src kinase and Toll-like receptor 4 and proinflammatory changes, including increased nuclear factor kappa-light-chain-enhancer of activated B cells activation, secretion of proinflammatory chemokines (i.e., monocyte chemotactic protein 1 and interleukin-8), as well as alterations of the F-actin cytoskeleton. Treatment with Src inhibitor (4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyramidine) decreased the inflammatory changes and improved cytoskeletal defects. Inhibition of Src, along with administration of VX-770 and VX-809, successfully restored fluid secretion to normal levels. CONCLUSION Our findings have strong translational potential and indicate that targeting Src kinase and decreasing inflammation may increase the efficacy of pharmacological therapies aimed at correcting the basic ΔF508 defect in CF liver patients. These studies also demonstrate the promise of applying iPSC technology in modeling human cholangiopathies. (Hepatology 2018;67:972-988).
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Affiliation(s)
- Romina Fiorotto
- Section of Digestive Diseases, Liver Center, Yale University, New Haven, CT, USA
- International Center for Digestive Health, University of Milan-Bicocca, Milan, Italy
| | - Mariangela Amenduni
- Section of Digestive Diseases, Liver Center, Yale University, New Haven, CT, USA
| | - Valeria Mariotti
- Department of Molecular Medicine, University of Padua, School of Medicine, Padua, Italy
| | - Luca Fabris
- Department of Molecular Medicine, University of Padua, School of Medicine, Padua, Italy
| | - Carlo Spirli
- Section of Digestive Diseases, Liver Center, Yale University, New Haven, CT, USA
- International Center for Digestive Health, University of Milan-Bicocca, Milan, Italy
| | - Mario Strazzabosco
- Section of Digestive Diseases, Liver Center, Yale University, New Haven, CT, USA
- International Center for Digestive Health, University of Milan-Bicocca, Milan, Italy
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Quaglia A, Roberts EA, Torbenson M. Developmental and Inherited Liver Disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2018:111-274. [DOI: 10.1016/b978-0-7020-6697-9.00003-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Russo P. Liver Disease in Cystic Fibrosis. PRACTICAL HEPATIC PATHOLOGY: A DIAGNOSTIC APPROACH 2018:143-150. [DOI: 10.1016/b978-0-323-42873-6.00010-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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15
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Conese M, Beccia E, Castellani S, Di Gioia S, Colombo C, Angiolillo A, Carbone A. The long and winding road: stem cells for cystic fibrosis. Expert Opin Biol Ther 2017; 18:281-292. [PMID: 29216777 DOI: 10.1080/14712598.2018.1413087] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
INTRODUCTION Cystic fibrosis (CF) is a genetic syndrome with a high mortality rate due to severe lung disease. Despite having several drugs targeting specific mutated CFTR proteins already in clinical trials, new therapies, based on stem cells, are also emerging to treat those patients. AREAS COVERED The authors review the main sources of stem cells, including embryonic stem cells (ESCs), induced-pluripotent stem cells (iPSCs), gestational stem cells, and adult stem cells, such as mesenchymal stem cells (MSCs) in the context of CF. Furthermore, they describe the main animal and human models of lung physiology and pathology, involved in the optimization of these stem cell-applied therapies in CF. EXPERT OPINION ESCs and iPSCs are emerging sources for disease modeling and drug discovery purposes. The allogeneic transplant of healthy MSCs, that acts independently to specific mutations, is under intense scrutiny due to their secretory, immunomodulatory, anti-inflammatory and anti-bacterial properties. The main challenge for future developments will be to get exogenous stem cells into the appropriate lung location, where they can regenerate endogenous stem cells and act as inflammatory modulators. The clinical application of stem cells for the treatment of CF certainly warrants further insight into pre-clinical models, including large animals, organoids, decellularized organs and lung bioengineering.
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Affiliation(s)
- Massimo Conese
- a Laboratory of Experimental and Regenerative Medicine, Department of Medical and Surgical Sciences , University of Foggia , Foggia , Italy
| | - Elisa Beccia
- a Laboratory of Experimental and Regenerative Medicine, Department of Medical and Surgical Sciences , University of Foggia , Foggia , Italy.,b Department of Medicine and Health Sciences 'V. Tiberio' , University of Molise , Campobasso , Italy
| | - Stefano Castellani
- a Laboratory of Experimental and Regenerative Medicine, Department of Medical and Surgical Sciences , University of Foggia , Foggia , Italy
| | - Sante Di Gioia
- a Laboratory of Experimental and Regenerative Medicine, Department of Medical and Surgical Sciences , University of Foggia , Foggia , Italy
| | - Carla Colombo
- c Cystic Fibrosis Center, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Department of Pathophysiology and Transplantation , University of Milan , Milan , Italy
| | - Antonella Angiolillo
- b Department of Medicine and Health Sciences 'V. Tiberio' , University of Molise , Campobasso , Italy
| | - Annalucia Carbone
- d Division of Internal Medicine and Chronobiology Unit , IRCCS 'Casa Sollievo della Sofferenza' , San Giovanni Rotondo (FG) , Italy
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Drzymała-Czyż S, Szczepanik M, Krzyżanowska P, Duś-Żuchowska M, Pogorzelski A, Sapiejka E, Juszczak P, Lisowska A, Koletzko B, Walkowiak J. Serum Phospholipid Fatty Acid Composition in Cystic Fibrosis Patients with and without Liver Cirrhosis. ANNALS OF NUTRITION AND METABOLISM 2017; 71:91-98. [DOI: 10.1159/000477913] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/05/2017] [Accepted: 05/25/2017] [Indexed: 12/25/2022]
Abstract
Background/Aims: Cystic fibrosis (CF) liver disease is the third most frequent cause of death in CF patients. Although it alters fatty acid (FA) metabolism, data concerning the profile of FA in CF patients with liver cirrhosis is lacking. This study aimed to assess the FA composition of serum phospholipids in CF patients with and without liver cirrhosis. Methods: The study comprised 25 CF patients with liver cirrhosis and 25 without it. We assessed Z-scores for body height and weight, lung function, exocrine pancreatic sufficiency and colonization with Pseudomonas aeruginosa. FAs' profile of serum glycerophospholipids was quantified by gas chromatography mass spectrometry. Results: In CF patients with liver cirrhosis, the levels of C16:0 were higher and the amounts of C20:2n-6, C20:3n-6, C20:4n-6, and all the n-3 polyunsaturated FAs (PUFAs) (C18:3n-3, C20:5n-3, C22:5n-3, C22:6n-3) were lower than those in CF subjects without liver cirrhosis. The n-6/n-3, C20:4n-6/C18:2n-6, total n-6/C18:2n-6, C20:5n-3/C18:3n-3 and total n-3/C18:3n-3 ratios did not differ between the 2 groups. Conclusions: Liver cirrhosis may associate with profound abnormalities in the composition of serum glycerophospholipids FAs in CF patients. None of the analyzed clinical factors could explain the greater prevalence of low levels of PUFAs in this CF subgroup.
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Relevance of 3D Cholangiography and Transient Elastography to Assess Cystic Fibrosis-Associated Liver Disease? Can Respir J 2016; 2016:4592702. [PMID: 27445541 PMCID: PMC4939173 DOI: 10.1155/2016/4592702] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Revised: 05/25/2016] [Accepted: 06/02/2016] [Indexed: 12/14/2022] Open
Abstract
Background. Cystic fibrosis-associated liver disease (CFLD) is a major cause of death. The objective of our retrospective study was to describe the relevance of magnetic resonance imaging (MRI) and liver stiffness measurement (LSM) for CFLD evaluation. Methods. All cystic fibrosis adult patients evaluated by MRI and LSM were included. MR signs of portal hypertension (PHT), dysmorphia, or cholangitis were collected and LSM expressed in kPa and Metavir. Results. Of 25 patients, 52% had abnormal MRI. Median LSM was 5.7 kPa (3.4–9.9). Three patients had F2 score and one had F3 score. In patients with PHT, LSM was 7.85 kPa (3.7–9.9) compared to 5 (3.4–7.5) in others, p = 0.02. In patients with abnormal liver function tests, 50% had increased LSM (≥F2), whereas 94% with normal tests had normal LSM (p = 0.04). Seven patients had abnormal MRI despite normal ultrasonography. Conclusions. MRI and LSM provide useful information on CFLD and may help to screen patients with PHT.
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Javitt NB. History of hepatic bile formation: old problems, new approaches. ADVANCES IN PHYSIOLOGY EDUCATION 2014; 38:279-285. [PMID: 25434010 DOI: 10.1152/advan.00076.2014] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
Studies of hepatic bile formation reported in 1958 established that it was an osmotically generated water flow. Intravenous infusion of sodium taurocholate established a high correlation between hepatic bile flow and bile acid excretion. Secretin, a hormone that stimulates bicarbonate secretion, was also found to increase hepatic bile flow. The sources of the water entering the biliary system with these two stimuli were differentiated by the use of mannitol. An increase in its excretion parallels the increase in bile flow in response to bile acids but not secretin, which led to a quantitative distinction between canalicular and ductular water flow. The finding of aquaglyceroporin-9 in the basolateral surface of the hepatocyte accounted for the rapid entry of mannitol into hepatocytes and its exclusion from water movement in the ductules where aquaporin-1 is present. Electron microscopy demonstrated that bile acids generate the formation of vesicles that contain lecithin and cholesterol after their receptor-mediated canalicular transport. Biophysical studies established that the osmotic effect of bile acids varies with their concentration and also with the proportion of mono-, di-, and trihydroxy bile acids and provides a basis for understanding their physiological effects. Because of the varying osmotic effect of bile acids, it is difficult to quantify bile acid independent flow generated by other solutes, such as glutathione, which enters the biliary system. Monohydroxy bile acids, by markedly increasing aggregation number, severely reduce water flow. Developing biomarkers for the noninvasive assessment of normal hepatic bile flow remains an elusive goal that merits further study.
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Affiliation(s)
- Norman B Javitt
- Department of Medicine, New York University School of Medicine, New York, New York
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Wlcek K, Stieger B. ATP-binding cassette transporters in liver. Biofactors 2014; 40:188-98. [PMID: 24105869 DOI: 10.1002/biof.1136] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2013] [Revised: 07/31/2013] [Accepted: 08/01/2013] [Indexed: 01/13/2023]
Abstract
The human ATP-binding cassette (ABC) superfamily consists of 48 members with 14 of them identified in normal human liver at the protein level. Most of the ABC members act as ATP dependent efflux transport systems. In the liver, ABC transporters are involved in diverse physiological processes including export of cholesterol, bile salts, and metabolic endproducts. Consequently, impaired ABC transporter function is involved in inherited diseases like sitosterolemia, hyperbilirubinemia, or cholestasis. Furthermore, altered expression of some of the hepatic ABCs have been associated with primary liver tumors. This review gives a short overview about the function of hepatic ABCs. Special focus is addressed on the localization and ontogenesis of ABC transporters in the human liver. In addition, their expression pattern in primary liver tumors is discussed.
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Affiliation(s)
- Katrin Wlcek
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, Switzerland
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20
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Parisi GF, Di Dio G, Franzonello C, Gennaro A, Rotolo N, Lionetti E, Leonardi S. Liver disease in cystic fibrosis: an update. HEPATITIS MONTHLY 2013; 13:e11215. [PMID: 24171010 PMCID: PMC3810678 DOI: 10.5812/hepatmon.11215] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/14/2013] [Revised: 06/16/2013] [Accepted: 08/05/2013] [Indexed: 12/11/2022]
Abstract
CONTEXT Cystic fibrosis (CF) is the most widespread autosomal recessive genetic disorder that limits life expectation amongst the Caucasian population. As the median survival has increased related to early multidisciplinary intervention, other manifestations of CF have emerged especially for the broad spectrum of hepatobiliary involvement. The present study reviews the existing literature on liver disease in cystic fibrosis and describes the key issues for an adequate clinical evaluation and management of patients, with a focus on the pathogenetic, clinical and diagnostic-therapeutic aspects of liver disease in CF. EVIDENCE ACQUISITION A literature search of electronic databases was undertaken for relevant studies published from 1990 about liver disease in cystic fibrosis. The databases searched were: EMBASE, PubMed and Cochrane Library. RESULTS CF is due to mutations in the gene on chromosome 7 that encodes an amino acidic polypeptide named CFTR (cystic fibrosis transmembrane regulator). The hepatic manifestations include particular changes referring to the basic CFTR defect, iatrogenic lesions or consequences of the multisystem disease. Even though hepatobiliary disease is the most common non-pulmonary cause of mortality in CF (the third after pulmonary disease and transplant complications), only about the 33%of CF patients presents clinically significant hepatobiliary disease. CONCLUSIONS Liver disease will have a growing impact on survival and quality of life of cystic fibrosis patients because a longer life expectancy and for this it is important its early recognition and a correct clinical management aimed at delaying the onset of complications. This review could represent an opportunity to encourage researchers to better investigate genotype-phenotype correlation associated with the development of cystic fibrosis liver disease, especially for non-CFTR genetic polymorphisms, and detect predisposed individuals. Therapeutic trials are needed to find strategies of fibrosis prevention and to avoid its progression prior to development its related complications.
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Affiliation(s)
- Giuseppe Fabio Parisi
- Department of Medical and Pediatric Science, Bronchopneumology and Cystic Fibrosis Unit, University of Catania, Catania, Italy
| | - Giovanna Di Dio
- Department of Medical and Pediatric Science, Bronchopneumology and Cystic Fibrosis Unit, University of Catania, Catania, Italy
| | - Chiara Franzonello
- Department of Medical and Pediatric Science, Bronchopneumology and Cystic Fibrosis Unit, University of Catania, Catania, Italy
| | - Alessia Gennaro
- Department of Medical and Pediatric Science, Bronchopneumology and Cystic Fibrosis Unit, University of Catania, Catania, Italy
| | - Novella Rotolo
- Department of Medical and Pediatric Science, Bronchopneumology and Cystic Fibrosis Unit, University of Catania, Catania, Italy
| | - Elena Lionetti
- Department of Medical and Pediatric Science, Bronchopneumology and Cystic Fibrosis Unit, University of Catania, Catania, Italy
| | - Salvatore Leonardi
- Department of Medical and Pediatric Science, Bronchopneumology and Cystic Fibrosis Unit, University of Catania, Catania, Italy
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Abstract
Despite the inclusion of extra vitamin D in their regimen of fat-soluble vitamin supplementation, cystic fibrosis patients remain chronically depleted of vitamin D. The persistence of suboptimal vitamin D status is often blamed on the maldigestion and malabsorption of fat. However, the mitigated success of recent clinical trials with high-dose vitamin D supplementation suggests that vitamin D bioavailability might be impaired in these patients. Given the growing understanding of the importance of this vitamin in the regulation of multiple biological functions beyond skeletal health, the present review analyzes the current literature by addressing each step of vitamin D metabolism and action in the context of this life-limiting pathology. In addition, it highlights the importance of vitamin D in relation to organs and or conditions affected by cystic fibrosis.
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Affiliation(s)
- Geneviève Mailhot
- Research Centre, CHU Sainte-Justine, Department of Nutrition, Université de Montréal, Montréal, Canada.
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22
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Abstract
OBJECTIVES Liver disease contributes to significant morbidity and mortality in cystic fibrosis (CF). Although all patients with CF express the defective CF transmembrane conductance regulator in cholangiocytes, many develop asymptomatic fibrosing liver disease. Only some develop cirrhosis, with pathogenesis remaining enigmatic. Available noninvasive diagnostic tools do not identify patients at risk before development of advanced fibrosis. We conducted a pilot study to identify genes associated with hepatic injury and fibrosis on liver biopsy that may help elucidate determinants of CF-associated liver disease (CFLD). METHODS Liver tissue from children with CFLD with various stages of hepatic fibrosis was compared with pediatric controls using cDNA array analysis. Differential expression of genes of interest was then assessed relative to pediatric control liver and non-CF cholestatic disease control liver from patients with biliary atresia, using both real-time reverse transcription-polymerase chain reaction and immunohistochemistry. RESULTS cDNA array demonstrated differential expression of numerous genes associated with hepatic fibrogenesis including collagens, matrix metalloproteinases, and chemokines in CFLD versus normal controls, particularly decreased expression in tissue remodeling genes including plasminogen activator inhibitor-1 (PAI-1, up to 25-fold) and tissue inhibitor of metalloproteinase-1 (TIMP-1); this was validated by real-time reverse transcription-polymerase chain reaction (PAI-1, P = 0.004; TIMP-1, P = 0.019). No significant decrease in PAI-1 or TIMP-1 mRNA was observed in biliary atresia versus normal control. Immunohistochemistry confirmed the decreased expression of hepatic PAI-1 and TIMP-1 protein in CFLD versus both normal and biliary atresia disease controls. CONCLUSIONS The coordinated differential expression of these genes associated with liver fibrosis provides evidence for a transcriptional basis for the pathogenesis of CFLD and provides avenues for further study. Clarifying the pathogenesis of CFLD will facilitate techniques for early, precirrhotic detection and targeted interventions.
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Lewindon PJ, Shepherd RW, Walsh MJ, Greer RM, Williamson R, Pereira TN, Frawley K, Bell SC, Smith JL, Ramm GA. Importance of hepatic fibrosis in cystic fibrosis and the predictive value of liver biopsy. Hepatology 2011; 53:193-201. [PMID: 21254170 DOI: 10.1002/hep.24014] [Citation(s) in RCA: 73] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2010] [Accepted: 09/10/2010] [Indexed: 12/25/2022]
Abstract
UNLABELLED Cystic fibrosis liver disease (CFLD), which results from progressive hepatobiliary fibrosis, is an important cause of morbidity and mortality, but it is difficult to identify before portal hypertension (PHT) ensues. Clinical signs, serum alanine aminotransferase (ALT) levels, and ultrasound (US) are widely applied, but their value in predicting the presence of cirrhosis, the development of PHT, or adverse outcomes is undetermined. The potential gold standard, liver biopsy, is not standard practice and, notwithstanding sampling error considerations, has not been systematically evaluated. Forty patients with cystic fibrosis (median age = 10.6 years) with abnormal clinical, biochemical, and US findings were subjected to dual-pass percutaneous liver biopsy. Clinical outcomes were recorded over 12 years of follow-up (median = 9.5 years for survivors). Logistic regression and receiver operating characteristic analyses were applied to predict hepatic fibrosis (which was assessed by fibrosis staging and quantitative immunohistochemistry) and the occurrence of PHT. PHT occurred in 17 of 40 patients (42%), including 6 of 7 (17%) who died during follow-up. Clinical examination, serum ALT levels, and US findings failed to predict either the presence of liver fibrosis or the development of PHT. Fibrosis staging on liver biopsy, where the accuracy was improved by dual passes (P = 0.002, nonconcordance = 38%), predicted the development of PHT (P < 0.001), which occurred more frequently and at a younger age in those with severe fibrosis. CONCLUSION Clinical modalities currently employed to evaluate suspected CFLD help to identify a cohort of children at risk for liver disease and adverse outcomes but do not predict an individual's risk of liver fibrosis or PHT development. Liver fibrosis on biopsy predicts the development of clinically significant liver disease. Dual passes help to address sampling concerns. Liver biopsy has a relevant role in the management of patients with suspected CFLD and deserves more widespread application.
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Affiliation(s)
- Peter J Lewindon
- Department of Gastroenterology, Royal Children's Hospital, Brisbane, Queensland, Australia
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Gu X, Manautou JE. Regulation of hepatic ABCC transporters by xenobiotics and in disease states. Drug Metab Rev 2010; 42:482-538. [PMID: 20233023 DOI: 10.3109/03602531003654915] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
The subfamily of ABCC transporters consists of 13 members in mammals, including the multidrug resistance-associated proteins (MRPs), sulfonylurea receptors (SURs), and the cystic fibrosis transmembrane conductance regulator (CFTR). These proteins play roles in chemical detoxification, disposition, and normal cell physiology. ABCC transporters are expressed differentially in the liver and are regulated at the transcription and translation level. Their expression and function are also controlled by post-translational modification and membrane-trafficking events. These processes are tightly regulated. Information about alterations in the expression of hepatobiliary ABCC transporters could provide important insights into the pathogenesis of diseases and disposition of xenobiotics. In this review, we describe the regulation of hepatic ABCC transporters in humans and rodents by a variety of xenobiotics, under disease states and in genetically modified animal models deficient in transcription factors, transporters, and cell-signaling molecules.
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Affiliation(s)
- Xinsheng Gu
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, 06269, USA
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Bartlett JR, Friedman KJ, Ling SC, Pace RG, Bell SC, Bourke B, Castaldo G, Castellani C, Cipolli M, Colombo C, Colombo JL, Debray D, Fernandez A, Lacaille F, Macek M, Rowland M, Salvatore F, Taylor CJ, Wainwright C, Wilschanski M, Zemková D, Hannah WB, Phillips MJ, Corey M, Zielenski J, Dorfman R, Wang Y, Zou F, Silverman LM, Drumm ML, Wright FA, Lange EM, Durie PR, Knowles MR. Genetic modifiers of liver disease in cystic fibrosis. JAMA 2009; 302:1076-83. [PMID: 19738092 PMCID: PMC3711243 DOI: 10.1001/jama.2009.1295] [Citation(s) in RCA: 201] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
CONTEXT A subset (approximately 3%-5%) of patients with cystic fibrosis (CF) develops severe liver disease with portal hypertension. OBJECTIVE To assess whether any of 9 polymorphisms in 5 candidate genes (alpha(1)-antitrypsin or alpha(1)-antiprotease [SERPINA1], angiotensin-converting enzyme [ACE], glutathione S-transferase [GSTP1], mannose-binding lectin 2 [MBL2], and transforming growth factor beta1 [TGFB1]) are associated with severe liver disease in patients with CF. DESIGN, SETTING, AND PARTICIPANTS Two-stage case-control study enrolling patients with CF and severe liver disease with portal hypertension (CFLD) from 63 CF centers in the United States as well as 32 in Canada and 18 outside of North America, with the University of North Carolina at Chapel Hill as the coordinating site. In the initial study, 124 patients with CFLD (enrolled January 1999-December 2004) and 843 control patients without CFLD were studied by genotyping 9 polymorphisms in 5 genes previously studied as modifiers of liver disease in CF. In the second stage, the SERPINA1 Z allele and TGFB1 codon 10 genotype were tested in an additional 136 patients with CFLD (enrolled January 2005-February 2007) and 1088 with no CFLD. MAIN OUTCOME MEASURES Differences in distribution of genotypes in patients with CFLD vs patients without CFLD. RESULTS The initial study showed CFLD to be associated with the SERPINA1 Z allele (odds ratio [OR], 4.72; 95% confidence interval [CI], 2.31-9.61; P = 3.3 x 10(-6)) and with TGFB1 codon 10 CC genotype (OR, 1.53; 95% CI, 1.16-2.03; P = 2.8 x 10(-3)). In the replication study, CFLD was associated with the SERPINA1 Z allele (OR, 3.42; 95% CI, 1.54-7.59; P = 1.4 x 10(-3)) but not with TGFB1 codon 10. A combined analysis of the initial and replication studies by logistic regression showed CFLD to be associated with SERPINA1 Z allele (OR, 5.04; 95% CI, 2.88-8.83; P = 1.5 x 10(-8)). CONCLUSIONS The SERPINA1 Z allele is a risk factor for liver disease in CF. Patients who carry the Z allele are at greater risk (OR, approximately 5) of developing severe liver disease with portal hypertension.
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Cottart CH, Bonvin E, Rey C, Wendum D, Bernaudin JF, Dumont S, Lasnier E, Debray D, Clément A, Housset C, Bonora M. Impact of nutrition on phenotype in CFTR-deficient mice. Pediatr Res 2007; 62:528-32. [PMID: 17805210 DOI: 10.1203/pdr.0b013e318155a61d] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
To elucidate the impact of nutrition in cystic fibrosis (CF), we compared the phenotypic traits of Cftr -/- mice fed either a lipid-enriched liquid diet (Peptamen) or a standard chow combined with polyethylenglycol osmotic laxative (PEG), two strategies commonly used to prevent intestinal obstruction in CF mice. Survival, growth, liver, and ventilatory status were determined in Cftr -/- and Cftr +/+ mice, followed-up until 120 d. Ventilation was recorded in conscious animals using whole-body plethysmography. We found that the survival rate was similar in Peptamen and PEG Cftr -/- mice. Cftr -/- mice had lower minute ventilation than Cftr +/+ mice, whatever the diet. Both Cftr -/- and Cftr +/+ mice fed Peptamen displayed preadult growth delay compared with PEG-treated animals. Despite subsequent growth catch-up, Cftr -/- mice remained smaller than Cftr +/+ mice, whatever the diet. All Peptamen fed Cftr -/- mice showed hepatomegaly and liver steatosis, which also occurred but to a lesser extent in Peptamen fed Cftr +/+ animals. Therefore, while both treatment strategies are similarly efficient to avoid high mortality at weaning, Peptamen induces preadult growth delay and liver steatosis. These effects of diet are important to consider in future animal studies and also prompt to evaluate high-energy diets in CF patients.
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Perdue DG, Cass OW, Milla C, Dunitz J, Jessurun J, Sharp HL, Schwarzenberg SJ. Hepatolithiasis and cholangiocarcinoma in cystic fibrosis: a case series and review of the literature. Dig Dis Sci 2007; 52:2638-42. [PMID: 17443409 DOI: 10.1007/s10620-006-9259-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2006] [Accepted: 02/13/2006] [Indexed: 02/07/2023]
Affiliation(s)
- David G Perdue
- Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA
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Verhaeghe C, Delbecque K, de Leval L, Oury C, Bours V. Early inflammation in the airways of a cystic fibrosis foetus. J Cyst Fibros 2007; 6:304-8. [PMID: 17223612 DOI: 10.1016/j.jcf.2006.12.001] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2006] [Revised: 11/22/2006] [Accepted: 12/07/2006] [Indexed: 11/25/2022]
Abstract
In cystic fibrosis patients, inflammation is often considered to be secondary to chronic infections. In the present study, we show increased levels of pro-inflammatory proteins in the lungs of a cystic fibrosis foetus compared to the lungs of two normal foetuses. Our findings suggest therefore the existence of an early intrinsic pro-inflammatory state in cystic fibrosis airways.
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Affiliation(s)
- Catherine Verhaeghe
- Department of Human Genetics, Center for Biomedical Integrative Genoproteomics (CBIG), University of Liege, CHU Sart-Tilman B35, B-4000 Liege, Belgium
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Collardeau-Frachon S, Bouvier R, Le Gall C, Rivet C, Cabet F, Bellon G, Lachaux A, Scoazec JY. Unexpected diagnosis of cystic fibrosis at liver biopsy: a report of four pediatric cases. Virchows Arch 2007; 451:57-64. [PMID: 17554556 DOI: 10.1007/s00428-007-0434-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2007] [Revised: 05/02/2007] [Accepted: 05/06/2007] [Indexed: 10/23/2022]
Abstract
We report here four cases of pediatric patients in whom the diagnosis of cystic fibrosis was made only after the histological examination of a liver specimen obtained by biopsy (three cases) or at autopsy (one case). There were two boys and two girls, aged 13 months to 7.5 years. None had a personal or familial history suggestive of cystic fibrosis. One patient, presenting with myocardial lesion and hepatomegaly, died of heart failure; at autopsy, the liver showed a typical aspect of focal biliary cirrhosis. In the three other cases, liver disease was the only manifestation of cystic fibrosis at the time of diagnosis. Liver biopsy examination showed focal biliary cirrhosis in one case and massive steatosis in two. In all four cases, the diagnosis was confirmed by the existence of known pathogenic mutations in the CFTR gene. The evolution was variable; one patient had progressive liver disease with severe portal hypertension after 7 years; another one had lung complications after 1 year. In conclusion, our experience recalls that the diagnosis of cystic fibrosis must be considered in children presenting with unexplained liver disease; its confirmation by molecular techniques makes it possible to set up an appropriate follow-up.
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Affiliation(s)
- Sophie Collardeau-Frachon
- Hospices Civils de Lyon, Hôpital Edouard Herriot, Service Central d'Anatomie et Cytologie Pathologiques, Lyon, France.
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30
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Mrugacz M, Zak J, Bakunowicz-Lazarczyk A, Wysocka J, Kaczmarski M. ICAM-1 expression on conjunctival epithelial cells in patients with cystic fibrosis. CYTOMETRY PART B-CLINICAL CYTOMETRY 2007; 72:204-8. [PMID: 17328035 DOI: 10.1002/cyto.b.20159] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
BACKGROUND Cystic fibrosis is one of the most common lethal genetic conditions. The defect is due to mutations in a gene on chromosome 7, named the cystic fibrosis transmembrane regulator (CFTR), which functions as a chloride channel in epithelial membranes It is presumed that the disease affects all secretory epithelia including the eye. The objective of this study is to investigate the expression of intercellular adhesion molecule-1 (ICAM-1) by conjunctival epithelial cells of patients with cystic fibrosis and the correlation between of the expression of ICAM-1 and the grade of cystic fibrosis severity. METHODS Impression cytology specimens were collected in 24 patients with cystic fibrosis. Cells were processed for flow cytometry, by using monoclonal antibodies to ICAM-1. RESULTS A significant increase of ICAM-1 expression on epithelial cells was found in patients with cystic fibrosis when compared with normal eyes. A positive correlation between the ICAM-1 expression and severe clinical status of CF patients was also observed. CONCLUSIONS Our findings suggest that the inflammation appears to have a role in the pathogenesis of the ocular surface changes in patients with cystic fibrosis. ICAM-1 expression on conjunctival epithelial cells may be a marker of the inflammatory status in cystic fibrosis patients. The method described here reveal good repeatability and reliability for the analysis of the inflammatory markers on conjunctival epithelial cells and can be a useful tool in evaluating of the ocular findings and treatment interventions in patients with cystic fibrosis.
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Affiliation(s)
- Malgorzata Mrugacz
- Department of Pediatric Ophthalmology, Medical University of Bialystok, Bialystok, Poland.
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31
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Abstract
Liver involvement in Cystic Fibrosis (CF) is much less frequent than both pulmonary and pancreatic diseases that are present in 80-90% of CF patients; liver disease (LD) affects only one third of CF patients, however, because of the decreasing mortality from extrahepatic causes, its recognition and management is becoming a relevant clinical issue. Recent observations suggest that clinical expression of LD in CF may be influenced by genetic modifiers; their identification is an important issue because it may allow recognition of patients at risk for the development of LD at the time of diagnosis of CF and early institution of prophylactic strategies. Oral bile acid therapy, aimed at improving biliary secretion in terms of bile viscosity and bile acid composition, is currently the only available therapeutic approach for CF-associated LD. However, the impact of this therapy on the natural history of LD remains to be defined and long-term effectiveness on clinically relevant outcomes should be further investigated. Liver transplantation should be offered to CF patients with progressive liver failure and/or with life-threatening sequelae of portal hypertension, who also have mild pulmonary involvement that is expected to support long-term survival. The 1-year survival rate after transplantation in CF patients is approximately 80%, with beneficial effects on lung function, nutritional status, body composition and quality of life in most cases.
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Affiliation(s)
- Carla Colombo
- Department of Pediatrics, CF Center, Fondazione IRCCS, Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, University of Milan, Milan, Italy.
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Glaser S, Francis H, Demorrow S, Lesage G, Fava G, Marzioni M, Venter J, Alpini G. Heterogeneity of the intrahepatic biliary epithelium. World J Gastroenterol 2006; 12:3523-36. [PMID: 16773709 PMCID: PMC4087568 DOI: 10.3748/wjg.v12.i22.3523] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The objectives of this review are to outline the recent findings related to the morphological heterogeneity of the biliary epithelium and the heterogeneous pathophysiological responses of different sized bile ducts to liver gastrointestinal hormones and peptides and liver injury/toxins with changes in apoptotic, proliferative and secretory activities. The knowledge of biliary function is rapidly increasing because of the recognition that biliary epithelial cells (cholangiocytes) are the targets of human cholangiopathies, which are characterized by proliferation/damage of bile ducts within a small range of sizes. The unique anatomy, morphology, innervation and vascularization of the biliary epithelium are consistent with function of cholangiocytes within different regions of the biliary tree. The in vivo models [e.g., bile duct ligation (BDL), partial hepatectomy, feeding of bile acids, carbon tetrachloride (CCl4) or α-naphthylisothiocyanate (ANIT)] and the in vivo experimental tools [e.g., freshly isolated small and large cholangiocytes or intrahepatic bile duct units (IBDU) and primary cultures of small and large murine cholangiocytes] have allowed us to demonstrate the morphological and functional heterogeneity of the intrahepatic biliary epithelium. These models demonstrated the differential secretory activities and the heterogeneous apoptotic and proliferative responses of different sized ducts. Similar to animal models of cholangiocyte proliferation/injury restricted to specific sized ducts, in human liver diseases bile duct damage predominates specific sized bile ducts. Future studies related to the functional heterogeneity of the intrahepatic biliary epithelium may disclose new pathophysiological treatments for patients with cholangiopathies.
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Affiliation(s)
- Shannon Glaser
- Department of Medicine, Division of R&E, Scott and White Memorial Hospital and The Texas A&M University System Health Science Center College of Medicine, MRB, 702 South West H.K. Dodgen Loop, Temple, Texas 76504, USA.
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Kim JS, Jin Y, Lemasters JJ. Reactive oxygen species, but not Ca2+ overloading, trigger pH- and mitochondrial permeability transition-dependent death of adult rat myocytes after ischemia-reperfusion. Am J Physiol Heart Circ Physiol 2006; 290:H2024-34. [PMID: 16399872 DOI: 10.1152/ajpheart.00683.2005] [Citation(s) in RCA: 220] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
We investigated the role of pH, reactive oxygen species (ROS), Ca2+, and the mitochondrial permeability transition (MPT) in pH-dependent ischemia-reperfusion injury to adult rat myocytes. Myocytes were incubated in anoxic Krebs-Ringer-HEPES buffer at pH 6.2 for 3 h to simulate ischemia. To simulate reperfusion, myocytes were reoxygenated at pH 6.2 or 7.4 for 2 h. Some myocytes were treated with MPT blockers (cyclosporin A and N-methyl-4-isoleucine cyclosporin) and antioxidants (desferal, diphenylphenylene diamine, and 2-mercaptopropionyl glycine). Mitochondrial membrane potential, inner membrane permeabilization, and ROS formation were imaged with tetramethylrhodamine methyl ester, calcein, and chloromethyldichlorofluorescein diacetate, respectively. For Ca2+ imaging, myocytes were coloaded with rhod-2 and fluo-4 to evaluate mitochondrial and cytosolic Ca2+, respectively. After 10 min of reperfusion at pH 7.4, calcein redistributed across the mitochondrial inner membrane, an event preceded by mitochondrial ROS formation and accompanied by hypercontracture, mitochondrial depolarization, and then cell death. Acidotic reperfusion, antioxidants, and MPT blockers each prevented the MPT, depolarization, hypercontraction, and cell killing. Antioxidants, but neither MPT blockers nor acidotic reperfusion, inhibited ROS formation after reperfusion. Furthermore, anoxic reperfusion at pH 7.4 prevented cell death. Both mitochondrial and cytosolic Ca2+ increased during ischemia but recovered in the first minutes of reperfusion. Mitochondrial and cytosolic Ca2+ overloading again occurred late after reperfusion. This late Ca2+ overloading was blocked by MPT inhibition. Intramitochondrial Ca2+ chelation by cold loading/warm incubation of BAPTA did not prevent cell death after reperfusion. In conclusion, mitochondrial ROS, together with normalization of pH, promote MPT onset and subsequent myocyte death after reperfusion. In contrast, Ca2+ overloading appears to be the consequence of bioenergetic failure after the MPT and is not a factor promoting MPT onset.
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Affiliation(s)
- Jae-Sung Kim
- Department of Cell and Developmental Biology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7090, USA
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McKeon D, Day A, Parmar J, Alexander G, Bilton D. Hepatocellular carcinoma in association with cirrhosis in a patient with cystic fibrosis. J Cyst Fibros 2005; 3:193-5. [PMID: 15463908 DOI: 10.1016/j.jcf.2004.04.006] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2003] [Accepted: 04/16/2004] [Indexed: 02/07/2023]
Abstract
BACKGROUND Cystic fibrosis liver disease (CFLD) occurs in 37% of patients with CF. To date and to the best of our knowledge, there has not been a documented case of hepatocellular carcinoma in association with cirrhosis and CF. CASE REPORT A 32-year-old lady with cystic fibrosis (CF) presented for her annual review. She had been diagnosed with CFLD since early adolescence. A routine ultrasound of her liver revealed lesions consistent with hepatocellular carcinoma. This was confirmed on histology. She had no risk factors for hepatitis, and thorough investigation revealed no other cause for her chronic liver disease. She was also found to be pregnant at the time of diagnosis. Her tumour was considered too large for resection and liver transplantation and she was referred to a national centre for laser ablative therapy. CONCLUSION It is our concern that with the increased life expectancy of patients with CF and the chronic nature of CFLD that this may be an increasingly recognised complication amongst the CF adult population. Therefore, we have changed our practice to more intense surveillance of patients with established CFLD to incorporate biannual ultrasound imaging of the hepatic system and yearly serum concentration measurements of alpha-fetoprotein.
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Affiliation(s)
- D McKeon
- CF Unit, Papworth Hospital NHS Trust, Papworth Everard, Cambridge, UK
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35
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36
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Abstract
Animal models of cystic fibrosis, in particular several different mutant mouse strains obtained by homologous recombination, have contributed considerably to our understanding of CF pathology. In this review, we describe and compare the main phenotypic features of these models. Recent and possible future developments in this field are discussed.
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Affiliation(s)
- Bob J Scholte
- Department of Cell Biology, Erasmus Medical Centre, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands.
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37
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Idiopathic Pulmonary Fibrosis. Proceedings of the 1st Annual Pittsburgh International Lung Conference. October 2002. Am J Respir Cell Mol Biol 2003; 29:S1-105. [PMID: 12936907 DOI: 10.1165/rcmb.2003-0159su] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
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38
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Bettinardi N, Felicetta I, Tomasi PA, Colombo C. Carbohydrate 19-9 antigen is not a marker of liver disease in patients with cystic fibrosis. Clin Chem Lab Med 2003; 41:311-6. [PMID: 12705340 DOI: 10.1515/cclm.2003.050] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Serum concentration of carbohydrate 19-9 antigen (CA 19-9), a sensitive marker of pancreatic cancer and cholangiocarcinoma, increases in a variety of liver diseases due to higher production and release by bile duct cells. Biliary epithelial cells are primarily affected in liver disease associated with cystic fibrosis (CF), which develops in up to 30% of CF patients. Our aim was to evaluate the usefulness of serum CA 19-9 concentration as a test of liver involvement in CF. Serum concentration of CA 19-9, liver enzymes, bile acids, and total amylase was determined in 107 CF patients (49 with and 58 without liver disease) and 56 healthy subjects. Serum CA 19-9 concentration was significantly higher in CF patients (67 U/ml, 95% CI 53.5-80.5 U/ml) than in controls (11.8 U/ml, 95% CI 2.5-44 U/ml; p < 0.001) and in CF patients with liver disease (92.3 U/ml, 95% CI 75-109.5 U/ml) compared to CF patients without liver disease (46.6 U/ml, 95% CI 27.8-65.4 U/ml; p < 0.001). In CF patients, stepwise logistic regression analysis identified alanine aminotransferase, gamma-glutamyltranspeptidase, amylase, and CA 19-9 as the most useful predictors of liver disease (p < 0.0001). Receiver-operating characteristic (ROC) curve analysis revealed gamma-glutamyltranspeptidase and CA 19-9 as the best tests for identification of liver disease in CF patients; at a CA 19-9 cut-off arbitrarily fixed at 73 U/ml, positive and negative predictive value was 70% and 78%, respectively (sensitivity 57%, specificity 81%). To increase sensitivity to 94%, the cut-off had to be fixed at 31 U/ml, which corresponds to a specificity of only 36.2% (predictive value 33%). Our study indicates that measurement of the serum CA 19-9 concentration alone cannot be proposed as a reliable test of early hepatic involvement in CF.
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Affiliation(s)
- Nora Bettinardi
- Analysis Laboratory, Sesto San Giovanni Hospital, Milan, Italy.
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39
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Colombo C, Battezzati PM, Crosignani A, Morabito A, Costantini D, Padoan R, Giunta A. Liver disease in cystic fibrosis: A prospective study on incidence, risk factors, and outcome. Hepatology 2002. [PMID: 12447862 DOI: 10.1002/hep.1840360613] [Citation(s) in RCA: 156] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Incidence of liver disease (LD) associated with cystic fibrosis (CF) and its clinical characterization still is unsettled. We have assessed prospectively the incidence and risk factors of this complication, and its impact on the clinical course of CF. Between 1980 and 1990, we enrolled 177 CF patients without LD in a systematic clinical, laboratory, ultrasonography screening program of at least a 10-year duration. During a 14-year median follow-up (2,432 patient-years), 48 patients developed LD, with cirrhosis already present in 5. Incidence rate (number of cases per 100 patient-years) was 1.8% (95% confidence interval: 1.3-2.4), with sharp decline after the age of 10 years and higher risk in patients with a history of meconium ileus (incidence rate ratio, 5.5; 2.7-11), male sex (2.5; 1.3-4.9), or severe mutations (2.4; 1.2-4.8) at multivariate analysis. Incidence of cirrhosis was 4.5% (2.3-7.8) during a median period of 5 years from diagnosis of liver disease. Among the 17 cirrhotic patients, 13 developed portal hypertension, 4 developed esophageal varices, 1 developed liver decompensation requiring liver transplantation. Development of LD did not condition different mortality (death rate ratio, 0.4; 0.1-1.5) or higher incidence of other clinically relevant outcomes. In conclusion, LD is a relatively frequent and early complication of CF, whose detection should be focused at the first life decade in patients with history of meconium ileus, male sex, or severe genotype. Although LD does not condition a different clinical course of CF, in some patients it may progress rapidly and require liver transplantation.
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Affiliation(s)
- Carla Colombo
- CF Center, Department of Pediatrics, University of Milan, Italy.
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40
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Henrion-Caude A, Flamant C, Roussey M, Housset C, Flahault A, Fryer AA, Chadelat K, Strange RC, Clement A. Liver disease in pediatric patients with cystic fibrosis is associated with glutathione S-transferase P1 polymorphism. Hepatology 2002; 36:913-7. [PMID: 12297838 DOI: 10.1053/jhep.2002.35534] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/07/2022]
Abstract
Liver disease in patients with cystic fibrosis (CF) is inconstant and has not yet been clearly related to any specific risk factor. While the expression of cystic fibrosis transmembrane conductance regulator (CFTR) is restricted to the biliary epithelium in the liver, recent findings indicate that CFTR modulates reduced glutathione (GSH) transport and that CFTR dysfunction creates an imbalance in the antioxidant defense. Among liver detoxifying enzymes, the glutathione S-transferases (GSTs) play a key role in the protection against oxidative stress. Because oxidative injury contributes to the development of liver disease, we hypothesized that 2 members of the GST superfamily, GSTM1 and GSTP1, which are expressed in the biliary epithelium, could influence the hepatic status in patients with CF. The potential impact of GSTM1 and GSTP1 gene polymorphisms was assessed in 106 children with CF (mean age, 11.5 years). Based on polymerase chain reaction/restriction fragment length polymorphism analysis, we found that the frequency of GSTP1-Ile(105)/Ile(105) genotype was significantly higher in patients with CF with liver disease than in those without (P <.03). Among the youngest patients, aged 6 years, GSTP1-Ile(105)/Ile(105) genotype was associated with a 8-fold increase in the risk of liver disease compared with other GSTP1 genotypes (P =.002). No association between the GSTM1 genotype and liver status was documented. In conclusion, GSTP1-Ile(105)-encoding allele contributes to hepatic dysfunction in CF. Identification of this polymorphism may have prognostic value and prompt early treatment in patients with CF with an increased risk of liver disease.
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Abstract
Hepatocytes possess chloride channels at the plasma membrane and in multiple intracellular compartments. These channels are required for cell volume regulation and acidification of intracellular organelles. Evidence also supports a role of chloride channels in modulation of apoptosis and cell growth. Swelling- and Ca(2+)-activated chloride channels have been identified in hepatocyte plasma membranes, and chloride channels have been observed in the membranes of lysosomes, endosomes, Golgi, endoplasmic reticulum, mitochondria, and the nucleus. This review summarizes the functions of these channels and discusses the specific channel molecules they may represent. Chloride channel molecules shown to be expressed in hepatocytes include members of the ClC channel family (ClC-2, ClC-3, ClC-5, and ClC-7), members of the newly identified CLIC family of intracellular chloride channels (CLIC-1 and CLIC-4), the mitochondrial voltage-dependent anion channel, and a newly identified intracellular channel, MCLC (Mid-1 related chloride channel). Current understanding does not include a molecular identification of most of the observed channel functions, but details of the molecular properties of these channel molecules should allow future identification and further understanding of chloride channel function in hepatocytes.
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Affiliation(s)
- Xinhua Li
- Department of Physiology and Biophysics University of Texas Medical Branch, Galveston, Texas 77555-0641, USA.
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42
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Lewindon PJ, Pereira TN, Hoskins AC, Bridle KR, Williamson RM, Shepherd RW, Ramm GA. The role of hepatic stellate cells and transforming growth factor-beta(1) in cystic fibrosis liver disease. THE AMERICAN JOURNAL OF PATHOLOGY 2002; 160:1705-15. [PMID: 12000722 PMCID: PMC1850885 DOI: 10.1016/s0002-9440(10)61117-0] [Citation(s) in RCA: 88] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Liver disease causes significant morbidity and mortality from multilobular cirrhosis in patients with cystic fibrosis. Abnormal bile transport and biliary fibrosis implicate abnormal biliary physiology in the pathogenesis of cystic fibrosis-associated liver disease (CFLD), yet the mediators linking biliary events to fibrosis remain unknown. Activated hepatic stellate cells (HSCs) are the pre-eminent mediators of fibrosis in a range of hepatic disorders. The dominant stimulus for matrix production by HSCs is the cytokine transforming growth factor (TGF)-beta(1). In CFLD, the role of HSCs and the source of TGF-beta(1) have not been evaluated. Liver biopsy tissue obtained from 38 children with CFLD was analyzed. Activated HSCs, identified by co-localization of procollagen alpha(1)(I) mRNA and alpha-smooth muscle actin, were demonstrated as the cellular source of excess collagen production in the fibrosis surrounding the bile ducts and the advancing edge of scar tissue. TGF-beta protein and TGF-beta(1) mRNA expression were shown to be predominantly expressed by bile duct epithelial cells. TGF-beta(1) expression was significantly correlated with both hepatic fibrosis and the percentage of portal tracts showing histological abnormalities associated with CFLD. This study demonstrates a definitive role for HSCs in fibrogenesis associated with CFLD and establishes a potential mechanism for the induction of HSC collagen gene expression through the production of TGF-beta(1) by bile duct epithelial cells.
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Affiliation(s)
- Peter J Lewindon
- Department of Gastroenterology, Royal Children's Hospital, Brisbane, Australia
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43
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Abstract
The identification of the genes responsible for various genetic liver disorders lead to a better understanding of basic physiology of hepatic transport systems. In this review we focus on transport systems involved in the generation of bile and in the maintenance of copper homeostasis. Abnormal function of these transporters results in diseases like Wilson's disease, progressive familial cholestasis syndromes, Dubin-Johnson syndrome and cystic fibrosis. Beyond these well defined diseases, functional impairments of transport proteins may predispose to non-genetic diseases ranging from intrahepatic cholestasis of pregnancy to neurodegenerative disorders including Alzheimer's disease.
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Affiliation(s)
- Peter Ferenci
- Department of Internal Medicine IV, Gastroenterology and Hepatology, University of Vienna, Austria.
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44
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Häusler M, Heimann G, Biesterfeld S. Fibrosis: a general feature in cystic fibrosis? J Pediatr Gastroenterol Nutr 2002; 34:236-9. [PMID: 11840048 DOI: 10.1097/00005176-200202000-00026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Affiliation(s)
- M Häusler
- Department of Paediatrics, University Hospital RWTH Aachen, Germany.
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45
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Zsembery A, Jessner W, Sitter G, Spirlí C, Strazzabosco M, Graf J. Correction of CFTR malfunction and stimulation of Ca-activated Cl channels restore HCO3- secretion in cystic fibrosis bile ductular cells. Hepatology 2002; 35:95-104. [PMID: 11786964 DOI: 10.1053/jhep.2002.30423] [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: 12/15/2022]
Abstract
In view of the occurrence of hepatobiliary disorders in cystic fibrosis (CF) this study addresses the role of the cystic fibrosis transmembrane conductance regulator (CFTR) and of Ca(2+)-activated Cl(-) channels in promoting HCO3- secretion in bile ductular cells. Human cholangiocytes were isolated from control livers and from 1 patient with CF (DeltaF508/G542X mutations). Single channel and whole cell currents were analyzed by patch clamp techniques, and HCO3- secretion was determined by fluorometric analysis of the rate of recovery of intracellular pH following alkaline loading. In control cholangiocytes, both cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) catalytic subunit, activated CFTR Cl(-) channels that exhibited a nonrectifying conductance of 8 pS and appeared in clusters. Activation of Cl(-) current by cAMP was associated with an increase in the rate of HCO3- secretion. The basal rate of HCO3- secretion was lower in CF than in control cholangiocytes. In both control and CF cholangiocytes, raising intracellular Ca(2+) concentrations with ionomycin led to a parallel activation of Cl(-) current and HCO3- secretion. Consistent with reports that premature stop codon mutations (class I; e.g., G542X) can be read over by treatment with aminoglycoside antibiotics, exposure of CF cholangiocytes to gentamicin restored activation by cAMP of Cl(-) current and HCO3- secretion. The observation that activation of Ca(2+)-dependent Cl(-) channels can substitute for cystic fibrosis transmembrane conductance regulator (CFTR) in supporting HCO3- secretion and the efficacy of gentamicin in restoring CFTR function and HCO3- secretion in class I mutations are of potential clinical interest.
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Affiliation(s)
- Akos Zsembery
- Department of Pathophysiology, University of Vienna, Vienna, Austria
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46
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Rodrigues CM, Steer CJ. The therapeutic effects of ursodeoxycholic acid as an anti-apoptotic agent. Expert Opin Investig Drugs 2001; 10:1243-53. [PMID: 11772248 DOI: 10.1517/13543784.10.7.1243] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
The dihydroxy bile acid, ursodeoxycholic acid (UDCA), has been in widespread clinical use in the Western world since the mid 1980s, when it was initially used for gallstone dissolution [1,2] and subsequently for the treatment of chronic cholestatic liver diseases [3,4]. Many clinical trials of UDCA in a variety of cholestatic disorders established biochemical and clinical improvements, and most importantly showed a significant prolongation of transplant-free survival after four years of treatment with UDCA in patients with primary biliary cirrhosis [5]. Despite its clinical efficacy, the precise mechanism(s) by which UDCA improves liver function during cholestasis is still a matter of debate [6]. It was initially considered that the choleretic effect of UDCA, coupled with its ability to cause a marked shift in the composition of the bile acid pool towards hydrophilicity, accounted for its mechanism of action. In recent years, however, it has become evident that UDCA and its conjugated derivatives are capable of exerting direct effects at the cellular, subcellular, and molecular levels by stabilising cell membranes, affecting signal transduction pathways, and regulating immune responses. In addition, we have shown that UDCA plays a unique role in modulating the apoptotic threshold in both hepatic and non-hepatic cells [7-10]. The purpose of this article is to examine the mechanism(s) by which UDCA prevents apoptotic cell death associated with cholestasis. In addition, we will also review a potentially novel and, heretofore, unrecognised role of UDCA as a therapeutic agent in the treatment of non-liver diseases associated with increased levels of apoptosis as a pathogenesis of the disorder.
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Affiliation(s)
- C M Rodrigues
- Centro de Patogénese Molecular, Faculdade de Farmácia, University of Lisbon, Av. Forças Armadas, 1600-083 Lisbon, Portugal.
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47
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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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Sharma M, Benharouga M, Hu W, Lukacs GL. Conformational and temperature-sensitive stability defects of the delta F508 cystic fibrosis transmembrane conductance regulator in post-endoplasmic reticulum compartments. J Biol Chem 2001; 276:8942-50. [PMID: 11124952 DOI: 10.1074/jbc.m009172200] [Citation(s) in RCA: 175] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Deletion of phenylalanine at position 508 (DeltaF508) is the most common cystic fibrosis (CF)-associated mutation in the CF transmembrane conductance regulator (CFTR), a cAMP-regulated chloride channel. The consensus notion is that DeltaF508 imposes a temperature-sensitive folding defect and targets newly synthesized CFTR for degradation at endoplasmic reticulum (ER). A limited amount of CFTR activity, however, appears at the cell surface in the epithelia of homozygous DeltaF508 CFTR mice and patients, suggesting that the ER retention is not absolute in native tissues. To further elucidate the reasons behind the inability of DeltaF508 CFTR to accumulate at the plasma membrane, its stability was determined subsequent to escape from the ER, induced by reduced temperature and glycerol. Biochemical and functional measurements show that rescued DeltaF508 CFTR has a temperature-sensitive stability defect in post-ER compartments, including the cell surface. The more than 4-20-fold accelerated degradation rate between 37 and 40 degrees C is, most likely, due to decreased conformational stability of the rescued DeltaF508 CFTR, demonstrated by in situ protease susceptibility and SDS-resistant thermoaggregation assays. We propose that the decreased stability of the spontaneously or pharmacologically rescued mutant may contribute to its inability to accumulate at the cell surface. Thus, therapeutic efforts to correct the folding defect should be combined with stabilization of the native DeltaF508 CFTR.
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Affiliation(s)
- M Sharma
- Program in Lung and Cell Biology, Hospital for Sick Children, and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5G 1X8, Canada
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