|
1
|
Luo X, Lu LG. Progress in the Management of Patients with Cholestatic Liver Disease: Where Are We and Where Are We Going? J Clin Transl Hepatol 2024; 12:581-588. [PMID: 38974958 PMCID: PMC11224908 DOI: 10.14218/jcth.2023.00519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 03/27/2024] [Accepted: 04/11/2024] [Indexed: 07/09/2024] Open
Abstract
Cholestatic liver disease is a group of diseases in which bile acid accumulates in the liver for various reasons, resulting in abnormal liver biochemical indicators and histological damage. Cholestasis can be divided into intrahepatic cholestasis and extrahepatic cholestasis, which will contribute to liver damage and progress to liver fibrosis and cirrhosis. Primary biliary cholangitis (PBC) and primary sclerosing cholangitis are the two most typical cholestatic liver diseases. Ursodeoxycholic acid is currently the first-line treatment for PBC, while obeticholic acid, budesonide and fibrates have also shown good potential in the treatment of PBC. There are currently no official drugs approved to treat primary sclerosing cholangitis, and the use of ursodeoxycholic acid may have certain clinical benefits. At present, progress has been made in new treatment directions for cholestatic liver disease, including fibroblast growth factor 19, cholestyramine, S-adenosyl-L-methionine, steroid drugs, farnesoid X receptor agonists, and more. Considerable progress has been made in the management of cholestatic liver disease but there are still many opportunities and challenges. In this review, we summarized the recommended guidelines for the management of cholestatic disease and the progress of new drug research and development, in order to provide an important reference for the clinical practice of cholestatic liver disease.
Collapse
Affiliation(s)
- Xin Luo
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lun-Gen Lu
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| |
Collapse
|
|
2
|
Islam D, Israr I, Taleb MAB, Rao A, Yosief R, Sultana R, Sampaziotis F, Tysoe OC, Trauner M, Karpen SJ, Ghanekar A, Kamath BM. A novel model to study mechanisms of cholestasis in human cholangiocytes reveals a role for the SIPR2 pathway. Hepatol Commun 2024; 8:e0389. [PMID: 38407207 PMCID: PMC10898671 DOI: 10.1097/hc9.0000000000000389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 12/09/2023] [Indexed: 02/27/2024] Open
Abstract
BACKGROUND Ductular reactivity is central to the pathophysiology of cholangiopathies. Mechanisms underlying the reactive phenotype activation by exogenous inflammatory mediators and bile acids are poorly understood. METHODS Using human extrahepatic cholangiocyte organoids (ECOs) we developed an injury model emulating the cholestatic microenvironment with exposure to inflammatory mediators and various pathogenic bile acids. Moreover, we explored roles for the bile acid activated Sphingosine-1-phosphate receptor 2 (S1PR2) and potential beneficial effects of therapeutic bile acids UDCA and norUDCA. RESULTS Synergistic exposure to bile acids (taurocholic acid, glycocholic acid, glycochenodeoxycholic acid) and TNF-α for 24 hours induced a reactive state as measured by ECO diameter, proliferation, lactate dehydrogenase activity and reactive phenotype markers. While NorUDCA and UDCA treatments given 8 hours after injury induction both suppressed reactive phenotype activation and most injury parameters, proliferation was improved by NorUDCA only. Extrahepatic cholangiocyte organoid stimulation with S1PR2 agonist sphingosine-1-phosphate reproduced the cholangiocyte reactive state and upregulated S1PR2 downstream mediators; these effects were suppressed by S1PR2 antagonist JET-013 (JET), downstream mediator extracellular signal-regulated kinase 1/2 inhibitor, and by norUDCA or UDCA treatments. JET also partially suppressed reactive phenotype after bile acid injury. CONCLUSIONS We developed a novel model to study the reactive cholangiocyte state in response to pathological stimuli in cholestasis and demonstrated a contributory role of S1PR2 signaling in both injury and NorUDCA/UDCA treatments. This model is a valuable tool to further explore the pathophysiology of human cholangiopathies.
Collapse
Affiliation(s)
- Diana Islam
- Development & Stem Cell Biology program, Peter Gilligan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Izza Israr
- Development & Stem Cell Biology program, Peter Gilligan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Mohamed A. B. Taleb
- Development & Stem Cell Biology program, Peter Gilligan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Aditya Rao
- Development & Stem Cell Biology program, Peter Gilligan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Robel Yosief
- Development & Stem Cell Biology program, Peter Gilligan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Rukhsar Sultana
- Development & Stem Cell Biology program, Peter Gilligan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Fotios Sampaziotis
- Wellcome–MRC Cambridge Stem Cell Institute, Department of Medicine, University of Cambridge, Cambridge, Cambridgeshire, UK
- Department of Medicine, University of Cambridge, Cambridge, Cambridgeshire, UK
| | - Olivia C. Tysoe
- Wellcome–MRC Cambridge Stem Cell Institute, Department of Medicine, University of Cambridge, Cambridge, Cambridgeshire, UK
| | - Michael Trauner
- Hans Popper Laboratory of Molecular Hepatology, Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Saul J. Karpen
- Division of Pediatric Gastroenterology, Department of Pediatrics, Hepatology, and Nutrition, Children’s Healthcare of Atlanta and Emory University School of Medicine, Atlanta, Georgia, USA
| | - Anand Ghanekar
- Division of General Surgery, Department of Surgery, University Health Network & The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Binita M. Kamath
- Development & Stem Cell Biology program, Peter Gilligan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, The Hospital for Sick Children and the University of Toronto, Toronto, Canada
| |
Collapse
|
|
3
|
Marchianò S, Biagioli M, Roselli R, Zampella A, Di Giorgio C, Bordoni M, Bellini R, Urbani G, Morretta E, Monti MC, Distrutti E, Fiorucci S. Beneficial effects of UDCA and norUDCA in a rodent model of steatosis are linked to modulation of GPBAR1/FXR signaling. Biochim Biophys Acta Mol Cell Biol Lipids 2022; 1867:159218. [PMID: 35985473 DOI: 10.1016/j.bbalip.2022.159218] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 07/25/2022] [Accepted: 08/09/2022] [Indexed: 12/12/2022]
Abstract
Non-alcoholic steatosis (NAFLD) and steatohepatitis (NASH) are two highly prevalent human disorders for which therapy remains suboptimal. Bile acids play an essential role in regulating liver metabolism, and several bile acids-based therapy are currently investigated for their potential therapeutic efficacy in NAFLD/NASH. Bile acids exert their functions, at least in part, by modulating two main receptors the Farnesoid-x-receptor (FXR) and the G protein-coupled receptor, GPBAR1. In the present study we have compared the pharmacological effects of two bile acids, the ursodeoxycholic acid (UDCA) and its derivative norUDCA, in a model of NAFLD/NASH induced by feeding mice with a Western diet for 12 weeks. The results of these studies demonstrated that both UDCA and norUDCA protected against development of steatosis and fibrosis, but did not reduce the hepatocytes ballooning nor the development of a pro-atherogenic lipid profile. Both agents reduced liver lipogenesis and ameliorated insulin sensitivity and adipocytes signaling as shown by increased expression of adiponectin. Mechanistically, UDCA acts as weak GPBAR1 agonist, while norUDCA exerted no effect on both GPBAR1 and FXR. In vivo administration of UDCA resets bile acid synthesis and promotes a shift toward bile acids species that are GPBAR1 agonists, UDCA, TUDCA and hyodeoxycholic acid, and increases GLP1 expression in the ileum. In contrast norUDCA is poorly metabolized exerting a minimal impact on GPBAR1 signaling. Together, these data, highlight the potential role of UDCA and norUDCA in treating of NAFLD, though these beneficial effects are supported by different mechanisms.
Collapse
Affiliation(s)
- Silvia Marchianò
- University of Perugia, Department of Medicine and Surgery, Perugia, Italy
| | - Michele Biagioli
- University of Perugia, Department of Medicine and Surgery, Perugia, Italy
| | - Rosalinda Roselli
- University of Naples Federico II, Department of Pharmacy, Naples, Italy
| | - Angela Zampella
- University of Naples Federico II, Department of Pharmacy, Naples, Italy
| | | | - Martina Bordoni
- University of Perugia, Department of Medicine and Surgery, Perugia, Italy
| | - Rachele Bellini
- University of Perugia, Department of Medicine and Surgery, Perugia, Italy
| | - Ginevra Urbani
- University of Perugia, Department of Medicine and Surgery, Perugia, Italy
| | - Elva Morretta
- Department of Pharmacy, University of Salerno, Italy
| | | | | | - Stefano Fiorucci
- University of Perugia, Department of Medicine and Surgery, Perugia, Italy.
| |
Collapse
|
|
4
|
Abstract
Bile acids wear many hats, including those of an emulsifier to facilitate nutrient absorption, a cholesterol metabolite, and a signaling molecule in various tissues modulating itching to metabolism and cellular functions. Bile acids are synthesized in the liver but exhibit wide-ranging effects indicating their ability to mediate organ-organ crosstalk. So, how does a steroid metabolite orchestrate such diverse functions? Despite the inherent chemical similarity, the side chain decorations alter the chemistry and biology of the different bile acid species and their preferences to bind downstream receptors distinctly. Identification of new modifications in bile acids is burgeoning, and some of it is associated with the microbiota within the intestine. Here, we provide a brief overview of the history and the various receptors that mediate bile acid signaling in addition to its crosstalk with the gut microbiota.
Collapse
Affiliation(s)
| | | | - Sayeepriyadarshini Anakk
- Correspondence: Sayeepriyadarshini Anakk, PhD, Department of Molecular & Integrative Physiology, University of Illinois at Urbana-Champaign, 506 S Mathews Ave, 453 Medical Sciences Bldg, Urbana, IL 61801, USA.
| |
Collapse
|
|
5
|
Role of bile acids and their receptors in gastrointestinal and hepatic pathophysiology. Nat Rev Gastroenterol Hepatol 2022; 19:432-450. [PMID: 35165436 DOI: 10.1038/s41575-021-00566-7] [Citation(s) in RCA: 208] [Impact Index Per Article: 69.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/03/2021] [Indexed: 02/06/2023]
Abstract
Bile acids (BAs) can regulate their own metabolism and transport as well as other key aspects of metabolic homeostasis via dedicated (nuclear and G protein-coupled) receptors. Disrupted BA transport and homeostasis results in the development of cholestatic disorders and contributes to a wide range of liver diseases, including nonalcoholic fatty liver disease and hepatocellular and cholangiocellular carcinoma. Furthermore, impaired BA homeostasis can also affect the intestine, contributing to the pathogenesis of irritable bowel syndrome, inflammatory bowel disease, and colorectal and oesophageal cancer. Here, we provide a summary of the role of BAs and their disrupted homeostasis in the development of gastrointestinal and hepatic disorders and present novel insights on how targeting BA pathways might contribute to novel treatment strategies for these disorders.
Collapse
|
|
6
|
Gao W, Li Z, Chu H, Yuan H, Hu L, Yao L, Zhang L, Wang W, Lin R, Yang L. Ursodeoxycholic Acid in Liver Cirrhosis: A Chinese Perspective. PHARMACOTHERAPY FOR LIVER CIRRHOSIS AND ITS COMPLICATIONS 2022:81-111. [DOI: 10.1007/978-981-19-2615-0_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
|
7
|
Bonus M, Häussinger D, Gohlke H. Liver cell hydration and integrin signaling. Biol Chem 2021; 402:1033-1045. [PMID: 33915604 DOI: 10.1515/hsz-2021-0193] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Accepted: 04/12/2021] [Indexed: 12/21/2022]
Abstract
Liver cell hydration (cell volume) is dynamic and can change within minutes under the influence of hormones, nutrients, and oxidative stress. Such volume changes were identified as a novel and important modulator of cell function. It provides an early example for the interaction between a physical parameter (cell volume) on the one hand and metabolism, transport, and gene expression on the other. Such events involve mechanotransduction (osmosensing) which triggers signaling cascades towards liver function (osmosignaling). This article reviews our own work on this topic with emphasis on the role of β1 integrins as (osmo-)mechanosensors in the liver, but also on their role in bile acid signaling.
Collapse
Affiliation(s)
- Michele Bonus
- Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitätsstr. 1, D-40225 Düsseldorf, Germany
| | - Dieter Häussinger
- Clinic for Gastroenterology, Hepatology, and Infectious Diseases, Heinrich Heine University Düsseldorf, Moorenstr. 5, D-40225 Düsseldorf, Germany
| | - Holger Gohlke
- Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitätsstr. 1, D-40225 Düsseldorf, Germany
- John von Neumann Institute for Computing (NIC), Jülich Supercomputing Centre (JSC), Wilhelm-Johnen-Str., D-52428 Jülich, Germany
- Institute of Biological Information Processing (IBI-7: Structural Biochemistry), and Institute of Bio- and Geosciences (IBG-4: Bioinformatics), Forschungszentrum Jülich GmbH, Wilhelm-Johnen-Str., D-52428 Jülich, Germany
| |
Collapse
|
|
8
|
Kroll T, Smits SHJ, Schmitt L. Monomeric bile acids modulate the ATPase activity of detergent-solubilized ABCB4/MDR3. J Lipid Res 2021; 62:100087. [PMID: 34022183 PMCID: PMC8233136 DOI: 10.1016/j.jlr.2021.100087] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 04/28/2021] [Accepted: 05/10/2021] [Indexed: 12/19/2022] Open
Abstract
ABCB4, also called multidrug-resistant protein 3 (MDR3), is an ATP binding cassette transporter located in the canalicular membrane of hepatocytes that specifically translocates phosphatidylcholine (PC) lipids from the cytoplasmic to the extracellular leaflet. Due to the harsh detergent effect of bile acids, PC lipids provided by ABCB4 are extracted into the bile. While it is well known that bile acids are the major extractor of PC lipids from the membrane into bile, it is unknown whether only PC lipid extraction is improved or whether bile acids also have a direct effect on ABCB4. Using in vitro experiments, we investigated the modulation of ATP hydrolysis of ABC by different bile acids commonly present in humans. We demonstrated that all tested bile acids stimulated ATPase activity except for taurolithocholic acid, which inhibited ATPase activity due to its hydrophobic nature. Additionally, we observed a nearly linear correlation between the critical micelle concentration and maximal stimulation by each bile acid, and that this modulation was maintained in the presence of PC lipids. This study revealed a large effect of 24-nor-ursodeoxycholic acid, suggesting a distinct mode of regulation of ATPase activity compared with other bile acids. In addition, it sheds light on the molecular cross talk of canalicular ABC transporters of the human liver.
Collapse
Affiliation(s)
- Tim Kroll
- Institute of Biochemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Sander H J Smits
- Institute of Biochemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Lutz Schmitt
- Institute of Biochemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
| |
Collapse
|
|
9
|
Slae M, Wilschanski M. Cystic fibrosis and the gut. Frontline Gastroenterol 2020; 12:622-628. [PMID: 34917319 PMCID: PMC8640436 DOI: 10.1136/flgastro-2020-101610] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 09/29/2020] [Accepted: 10/03/2020] [Indexed: 02/04/2023] Open
Abstract
Cystic fibrosis (CF) is a recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. The gene product, CFTR protein, has important manifestations in the intestine, pancreas and hepatobiliary system. Increased survival has caused CF to be primarily an adult disease today. Physicians must be knowledgeable as to the varied phenotype in the gastrointestinal tract. This review will outline the main gastrointestinal manifestations including a section on gastrointestinal malignancy in CF. Novel treatments treating the basic effect in CF are now being introduced and their effects on the gastrointestinal tract are discussed.
Collapse
Affiliation(s)
- Mordechai Slae
- Paediatric Gastroenterology, Hadassah University Hospital, Jerusalem, Israel
| | - Michael Wilschanski
- Paediatric Gastroenterology, Hadassah University Hospital, Jerusalem, Israel
| |
Collapse
|
|
10
|
Yokoda RT, Rodriguez EA. Review: Pathogenesis of cholestatic liver diseases. World J Hepatol 2020; 12:423-435. [PMID: 32952871 PMCID: PMC7475774 DOI: 10.4254/wjh.v12.i8.423] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 06/07/2020] [Accepted: 08/01/2020] [Indexed: 02/06/2023] Open
Abstract
Cholestatic liver diseases (CLD) begin to develop after an impairment of bile flow start to affect the biliary tree. Cholangiocytes actively participate in the liver response to injury and repair and the intensity of this reaction is a determinant factor for the development of CLD. Progressive cholangiopathies may ultimately lead to end-stage liver disease requiring at the end orthotopic liver transplantation. This narrative review will discuss cholangiocyte biology and pathogenesis mechanisms involved in four intrahepatic CLD: Primary biliary cholangitis, primary sclerosing cholangitis, cystic fibrosis involving the liver, and polycystic liver disease.
Collapse
Affiliation(s)
- Raquel T Yokoda
- Department of Anatomic and Clinical Pathology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY 10467, United States
| | - Eduardo A Rodriguez
- Department of Gastroenterology, Hepatology and Nutrition, University of Utah, Salt Lake City, UT 84132, United States
| |
Collapse
|
|
11
|
Evidence for functional selectivity in TUDC- and norUDCA-induced signal transduction via α 5β 1 integrin towards choleresis. Sci Rep 2020; 10:5795. [PMID: 32242141 PMCID: PMC7118123 DOI: 10.1038/s41598-020-62326-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Accepted: 03/02/2020] [Indexed: 01/06/2023] Open
Abstract
Functional selectivity is the ligand-specific activation of certain signal transduction pathways at a receptor and has been described for G protein-coupled receptors. However, it has not yet been described for ligands interacting with integrins without αI domain. Here, we show by molecular dynamics simulations that four side chain-modified derivatives of tauroursodeoxycholic acid (TUDC), an agonist of α5β1 integrin, differentially shift the conformational equilibrium of α5β1 integrin towards the active state, in line with the extent of β1 integrin activation from immunostaining. Unlike TUDC, 24-nor-ursodeoxycholic acid (norUDCA)-induced β1 integrin activation triggered only transient activation of extracellular signal-regulated kinases and p38 mitogen-activated protein kinase and, consequently, only transient insertion of the bile acid transporter Bsep into the canalicular membrane, and did not involve activation of epidermal growth factor receptor. These results provide evidence that TUDC and norUDCA exert a functional selectivity at α5β1 integrin and may provide a rationale for differential therapeutic use of UDCA and norUDCA.
Collapse
|
|
12
|
Prescher M, Kroll T, Schmitt L. ABCB4/MDR3 in health and disease – at the crossroads of biochemistry and medicine. Biol Chem 2019; 400:1245-1259. [DOI: 10.1515/hsz-2018-0441] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Accepted: 01/28/2019] [Indexed: 12/12/2022]
Abstract
Abstract
Several ABC transporters of the human liver are responsible for the secretion of bile salts, lipids and cholesterol. Their interplay protects the biliary tree from the harsh detergent activity of bile salts. Among these transporters, ABCB4 is essential for the translocation of phosphatidylcholine (PC) lipids from the inner to the outer leaflet of the canalicular membrane of hepatocytes. ABCB4 deficiency can result in altered PC to bile salt ratios, which led to intrahepatic cholestasis of pregnancy, low phospholipid associated cholelithiasis, drug induced liver injury or even progressive familial intrahepatic cholestasis type 3. Although PC lipids only account for 30–40% of the lipids in the canalicular membrane, 95% of all phospholipids in bile are PC lipids. We discuss this discrepancy in the light of PC synthesis and bile salts favoring certain lipids. Nevertheless, the in vivo extraction of PC lipids from the outer leaflet of the canalicular membrane by bile salts should be considered as a separate step in bile formation. Therefore, methods to characterize disease causing ABCB4 mutations should be considered carefully, but such an analysis represents a crucial point in understanding the currently unknown transport mechanism of this ABC transporter.
Collapse
|
|
13
|
Abstract
Bile acid biotransformation is a collaborative effort by the host and the gut microbiome. Host hepatocytes synthesize primary bile acids from cholesterol. Once these host-derived primary bile acids enter the gastrointestinal tract, the gut microbiota chemically modify them into secondary bile acids. Interest into the gut-bile acid-host axis is expanding in diverse fields including gastroenterology, endocrinology, oncology, and infectious disease. This review aims to 1) describe the physiologic aspects of collaborative bile acid metabolism by the host and gut microbiota; 2) to evaluate how gut microbes influence bile acid pools, and in turn how bile acid pools modulate the gut microbial community structure; 3) to compare species differences in bile acid pools; and lastly, 4) discuss the effects of ursodeoxycholic acid (UDCA) administration, a common therapeutic bile acid, on the gut microbiota-bile acid-host axis.
Collapse
Affiliation(s)
- Jenessa A. Winston
- Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA
| | - Casey M. Theriot
- Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA,CONTACT Casey M. Theriot Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Research Building 406, 1060 William Moore Drive, Raleigh, NC 27607, USA
| |
Collapse
|
|
14
|
[Immune-mediated cholangiopathies : Diagnostic and therapeutic challenges]. Radiologe 2019; 59:348-356. [PMID: 30874827 DOI: 10.1007/s00117-019-0513-x] [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: 10/27/2022]
Abstract
BACKGROUND Immune-mediated cholangiopathies comprise primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and IgG4-associated cholangitis (IAC). A common feature is the progressive destruction of bile ducts leading to cholestasis with fibrosis and cirrhosis of the liver over time. The diseases are mostly identified during routine laboratory testing. Clinical signs and symptoms such as pruritus, fatigue or jaundice are infrequent in the early stage. DIAGNOSIS The diagnostic work-up involves the patient's history, physical examination, serological tests, abdominal ultrasonography, magnetic resonance cholangiopancreatography (MRCP) and, where necessary, liver biopsy and genetic testing. THERAPY Ursodeoxycholic acid (UDCA) is an effective treatment of PBC. Second-line therapies in addition to UDCA for incomplete UDCA responders are obeticholic acid (OCA) and bezafibrate, whereby only OCA has received approval for this indication from American (Federal Drug Administration) and European (European Medicines Agency) authorities. In PSC, UDCA improves prognostic markers; dominant bile duct strictures are treated with endoscopic balloon dilatation. Despite therapy, liver transplantation is frequently necessary for PSC. The risk of developing cholangiocarcinoma, colon cancer, and gallbladder cancer is increased for patients with PSC. In contrast to PBC and PSC, IAC responds well to corticosteroids. Disease relapse, however, is common, making long-term treatment with low-dose prednisolone or azathioprine necessary.
Collapse
|
|
15
|
Cabrera D, Arab JP, Arrese M. UDCA, NorUDCA, and TUDCA in Liver Diseases: A Review of Their Mechanisms of Action and Clinical Applications. Handb Exp Pharmacol 2019; 256:237-264. [PMID: 31236688 DOI: 10.1007/164_2019_241] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Bile acids (BAs) are key molecules in generating bile flow, which is an essential function of the liver. In the last decades, there have been great advances in the understanding of BA physiology, and new insights have emerged regarding the role of BAs in determining cell damage and death in several liver diseases. This new knowledge has helped to better delineate the pathophysiology of cholestasis and the adaptive responses of hepatocytes to cholestatic liver injury as well as of the mechanisms of injury of biliary epithelia. In this context, therapeutic approaches for liver diseases using hydrophilic BA (i.e., ursodeoxycholic acid, tauroursodeoxycholic, and, more recently, norursodeoxycholic acid), have been revamped. In the present review, we summarize current experimental and clinical data regarding these BAs and its role in the treatment of certain liver diseases.
Collapse
Affiliation(s)
- Daniel Cabrera
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
- Departamento de Ciencias Químicas y Biológicas, Facultad de Salud, Universidad Bernardo O'Higgins, Santiago, Chile
| | - Juan Pablo Arab
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Marco Arrese
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
| |
Collapse
|
|
16
|
Ðanić M, Stanimirov B, Pavlović N, Goločorbin-Kon S, Al-Salami H, Stankov K, Mikov M. Pharmacological Applications of Bile Acids and Their Derivatives in the Treatment of Metabolic Syndrome. Front Pharmacol 2018; 9:1382. [PMID: 30559664 PMCID: PMC6287190 DOI: 10.3389/fphar.2018.01382] [Citation(s) in RCA: 76] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Accepted: 11/09/2018] [Indexed: 12/12/2022] Open
Abstract
Apart from well-known functions of bile acids in digestion and solubilization of lipophilic nutrients and drugs in the small intestine, the emerging evidence from the past two decades identified the role of bile acids as signaling, endocrine molecules that regulate the glucose, lipid, and energy metabolism through complex and intertwined pathways that are largely mediated by activation of nuclear receptor farnesoid X receptor (FXR) and cell surface G protein-coupled receptor 1, TGR5 (also known as GPBAR1). Interactions of bile acids with the gut microbiota that result in the altered composition of circulating and intestinal bile acids pool, gut microbiota composition and modified signaling pathways, are further extending the complexity of biological functions of these steroid derivatives. Thus, bile acids signaling pathways have become attractive targets for the treatment of various metabolic diseases and metabolic syndrome opening the new potential avenue in their treatment. In addition, there is a significant effort to unveil some specific properties of bile acids relevant to their intrinsic potency and selectivity for particular receptors and to design novel modulators of these receptors with improved pharmacokinetic and pharmacodynamic profiles. This resulted in synthesis of few semi-synthetic bile acids derivatives such as 6α-ethyl-chenodeoxycholic acid (obeticholic acid, OCA), norursodeoxycholic acid (norUDCA), and 12-monoketocholic acid (12-MKC) that are proven to have positive effect in metabolic and hepato-biliary disorders. This review presents an overview of the current knowledge related to bile acids implications in glucose, lipid and energy metabolism, as well as a potential application of bile acids in metabolic syndrome treatment with future perspectives.
Collapse
Affiliation(s)
- Maja Ðanić
- Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia
| | - Bojan Stanimirov
- Department of Biochemistry, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia
| | - Nebojša Pavlović
- Department of Pharmacy, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia
| | | | - Hani Al-Salami
- Biotechnology and Drug Development Research Laboratory, School of Pharmacy and Biomedical Sciences, Biosciences Research Precinct, Curtin Health Innovation Research Institute, Curtin University, Perth, WA, Australia
| | - Karmen Stankov
- Department of Biochemistry, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia
| | - Momir Mikov
- Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia
| |
Collapse
|
|
17
|
NorUDCA promotes degradation of α1-antitrypsin mutant Z protein by inducing autophagy through AMPK/ULK1 pathway. PLoS One 2018; 13:e0200897. [PMID: 30067827 PMCID: PMC6070232 DOI: 10.1371/journal.pone.0200897] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Accepted: 07/05/2018] [Indexed: 02/07/2023] Open
Abstract
Alpha-1 Antitrypsin (α1AT) Deficiency is a genetic disease in which accumulation of α1AT mutant Z (α1ATZ) protein in the ER of hepatocytes causes chronic liver injury, liver fibrosis, and hepatocellular carcinoma. No effective medical therapy is currently available for the disease. We previously found that norUDCA improves the α1AT deficiency associated liver disease by promoting autophagic degradation of α1ATZ protein in liver in a mouse model of the disease. The current study unravels the novel underlying cellular mechanism by which norUDCA modulates autophagy. HTOZ cells, modified from HeLa Tet-Off cells by transfection with the resulting pTRE1-ATZ plasmid and expressing mutant Z proteins, were studied in these experiments. The role of norUDCA in inducing autophagy, autophagy-mediated degradation of α1ATZ and the role of AMPK in norUDCA-induced autophagy were examined in the current report. NorUDCA promoted disposal of α1ATZ via autophagy-mediated degradation of α1ATZ in HTOZ cells. Activation of AMPK was required for norUDCA-induced autophagy and α1ATZ degradation. Moreover, mTOR/ULK1 was involved in norUDCA-induced AMPK activation and autophagy in HTOZ cells. Our results provide novel mechanistic insights into the therapeutic action of norUDCA in promoting the clearance of α1ATZ in vitro and suggest a novel therapeutic approach for the treatment of α1ATZ deficiency disease and its associated liver diseases.
Collapse
|
|
18
|
Kalani A, Tabibian JH, Lindor KD. Emerging therapeutic targets for primary sclerosing cholangitis. Expert Opin Orphan Drugs 2018. [DOI: 10.1080/21678707.2018.1490643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Affiliation(s)
- Amir Kalani
- Vatche and Tamar Manoukian Division of Digestive Diseases, UCLA Gastroenterology Fellowship Training Program, Los Angeles, CA, USA
| | - James H. Tabibian
- Division of Gastroenterology, Department of Medicine, Olive View-UCLA Medical Center, Sylmar, CA, USA
| | - Keith D. Lindor
- Professor of Medicine and Senior Advisor to the Provost, College of Health Solutions, Arizona State University, USA
| |
Collapse
|
|
19
|
Abstract
OBJECTIVES Hepatobiliary complications are a leading cause of morbidity and mortality in cystic fibrosis (CF) patients. Knowledge of the underlying pathological aspects and optimal clinical management is, however, sorely lacking. METHODS We provide a summary of the lectures given by international speakers at the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) monothematic conference on cystic fibrosis-related liver disease (CFLD) held in Paris in January 2016, to discuss the status of our current knowledge of liver disease in CF patients, to define the critical areas that need to be addressed, and to resolve actions to elucidate relevant mechanisms of disease to optimise future therapeutic options. CONCLUSIONS The need for a universal consensus on the definition of CFLD to clarify disease stage and to identify relevant biomarkers to assess disease severity was highlighted. A deeper understanding of the pathophysiology and prognostic factors for the long-term evolution of CFLD is fundamental to move forward and has a strong bearing on identifying potential treatments. Novel experimental models and new treatment options under investigation are discussed and offer hope for the near future of CFLD.
Collapse
|
|
20
|
[Chronic cholestatic liver diseases : Differential diagnosis, pathogenesis and current treatment in adults]. Internist (Berl) 2017; 58:805-825. [PMID: 28721532 DOI: 10.1007/s00108-017-0287-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
In the long-term course chronic cholestasis regularly leads to fibrotic restructuring and ultimately to functional failure of the liver, independent of the cause. Cholestatic diseases are often clinically asymptomatic. In order to avoid progression, early diagnosis of the underlying disease and a targeted therapy are therefore decisive. The differential diagnoses of chronic cholestasis are broad; therefore, algorithms are of assistance in the diagnostic work-up. A better understanding of the pathogenesis is now leading to the development of new therapeutic agents in addition to ursodeoxycholic acid, which has long been known for its anticholestatic effects. Obeticholic acid and, in the near future, bezafibrate are therapeutic options. The possibilities for genetic diagnostics of unclear cholestasis syndromes improve the understanding of the pathogenesis of many diseases and are being introduced increasingly earlier into the clinical routine.
Collapse
|
|
21
|
Li M, Cai SY, Boyer JL. Mechanisms of bile acid mediated inflammation in the liver. Mol Aspects Med 2017; 56:45-53. [PMID: 28606651 DOI: 10.1016/j.mam.2017.06.001] [Citation(s) in RCA: 179] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Revised: 05/26/2017] [Accepted: 06/07/2017] [Indexed: 02/07/2023]
Abstract
Bile acids are synthesized in the liver and are the major component in bile. Impaired bile flow leads to cholestasis that is characterized by elevated levels of bile acid in the liver and serum, followed by hepatocyte and biliary injury. Although the causes of cholestasis have been extensively studied, the molecular mechanisms as to how bile acids initiate liver injury remain controversial. In this chapter, we summarize recent advances in the pathogenesis of bile acid induced liver injury. These include bile acid signaling pathways in hepatocytes as well as the response of cholangiocytes and innate immune cells in the liver in both patients with cholestasis and cholestatic animal models. We focus on how bile acids trigger the production of molecular mediators of neutrophil recruitment and the role of the inflammatory response in this pathological process. These advances point to a number of novel targets where drugs might be judged to be effective therapies for cholestatic liver injury.
Collapse
Affiliation(s)
- Man Li
- The Liver Center, Yale University School of Medicine, New Haven, CT 06510, USA
| | - Shi-Ying Cai
- The Liver Center, Yale University School of Medicine, New Haven, CT 06510, USA
| | - James L Boyer
- The Liver Center, Yale University School of Medicine, New Haven, CT 06510, USA.
| |
Collapse
|
|
22
|
Ben Ameur S, Chabchoub I, Telmoudi J, Belfitouri Y, Rebah O, Lacaille F, Aloulou H, Mehrzi A, Hachicha M. Management of cholestatic pruritus in children with Alagille syndrome: Case report and literature review. Arch Pediatr 2017; 23:1247-1250. [PMID: 28492167 DOI: 10.1016/j.arcped.2016.09.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2016] [Revised: 05/18/2016] [Accepted: 09/23/2016] [Indexed: 11/17/2022]
Abstract
Alagille syndrome causes intractable pruritus and disfiguring xanthomas because of retained bile acids and cholesterol. Drug therapy in addition to surgical intervention may be effective in many patients in reducing serum bile acids, cholesterol levels, pruritus, and skin xanthomas. In this report, we describe a child with Alagille syndrome who presented with severe pruritus and xanthomas as a consequence of severe hypercholesterolemia and discuss the treatment modalities.
Collapse
Affiliation(s)
- S Ben Ameur
- Pediatric department, Hedi Chaker Hospital, El ain street km 0,5, 3029 Sfax, Tunisia; Faculty of medicine, university of Sfax, Tunisia.
| | - I Chabchoub
- Pediatric department, Hedi Chaker Hospital, El ain street km 0,5, 3029 Sfax, Tunisia
| | - J Telmoudi
- Pediatric department, Hedi Chaker Hospital, El ain street km 0,5, 3029 Sfax, Tunisia
| | - Y Belfitouri
- Pediatric department, Hedi Chaker Hospital, El ain street km 0,5, 3029 Sfax, Tunisia
| | - O Rebah
- Pediatric department, La Marsa Hospital, Tunis, Tunisia
| | - F Lacaille
- Hepatogastroenterology-nutrition unit, Hôpital Necker-Enfants-Malades, 149, rue de Sèvres, 75015 Paris, France
| | - H Aloulou
- Pediatric department, Hedi Chaker Hospital, El ain street km 0,5, 3029 Sfax, Tunisia
| | - A Mehrzi
- Pediatric department, La Marsa Hospital, Tunis, Tunisia
| | - M Hachicha
- Pediatric department, Hedi Chaker Hospital, El ain street km 0,5, 3029 Sfax, Tunisia
| |
Collapse
|
|
23
|
Perazzo H, Dufour JF. The therapeutic landscape of non-alcoholic steatohepatitis. Liver Int 2017; 37:634-647. [PMID: 27727520 DOI: 10.1111/liv.13270] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2016] [Accepted: 10/05/2016] [Indexed: 12/19/2022]
Abstract
Non-alcoholic steatohepatitis (NASH) is characterized by lobular inflammation and hepatocellular ballooning, and may be associated with liver fibrosis leading to cirrhosis and its complications. A pharmacological approach is necessary to treat NASH because of failure to change dietary habits and lifestyle in most patients. Insulin resistance with an increased release of free fatty acids, oxidative stress and activation of inflammatory cytokines seem to be key features for disease progression. Thiazolidinediones, such as pioglitazone and antioxidant agents, such as vitamin E, were the first pharmacological options to be evaluated for NASH. In recent years, several new molecules that target different pathways related to NASH pathogenesis, such as liver metabolic homeostasis, inflammation, oxidative stress and fibrosis, have been developed. Obeticholic acid (INT-747) and elafibranor (GFT-505) have provided promising results in phase IIb, randomized, placebo-controlled clinical trials and they are being evaluated in ongoing phase III studies. Most of the potential treatments for NASH are under investigation in phase II studies, with some at phase I. This diversity in possible treatments calls for a better understanding of NASH in order to enrich trial populations with patients more susceptible to progress and to respond. This manuscript aims to review the pharmacological NASH treatment landscape.
Collapse
Affiliation(s)
- Hugo Perazzo
- Evandro Chagas National Institute of Infectious Disease (INI)-Oswaldo Cruz Foundation (FIOCRUZ), Laboratory of clinical research on STD/AIDS, Manguinhos, Rio de Janeiro, Brazil
| | - Jean-François Dufour
- University Clinic for Visceral Surgery and Medicine, University of Bern, Inselspital, Bern, Switzerland.,Hepatology, Department of Clinical Research, University of Bern, Bern, Switzerland
| |
Collapse
|
|
24
|
Chávez-Talavera O, Tailleux A, Lefebvre P, Staels B. Bile Acid Control of Metabolism and Inflammation in Obesity, Type 2 Diabetes, Dyslipidemia, and Nonalcoholic Fatty Liver Disease. Gastroenterology 2017; 152:1679-1694.e3. [PMID: 28214524 DOI: 10.1053/j.gastro.2017.01.055] [Citation(s) in RCA: 646] [Impact Index Per Article: 80.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2016] [Revised: 01/19/2017] [Accepted: 01/20/2017] [Indexed: 02/06/2023]
Abstract
Bile acids are signaling molecules that coordinately regulate metabolism and inflammation via the nuclear farnesoid X receptor (FXR) and the Takeda G protein-coupled receptor 5 (TGR5). These receptors activate transcriptional networks and signaling cascades controlling the expression and activity of genes involved in bile acid, lipid and carbohydrate metabolism, energy expenditure, and inflammation by acting predominantly in enterohepatic tissues, but also in peripheral organs. In this review, we discuss the most recent findings on the inter-organ signaling and interplay with the gut microbiota of bile acids and their receptors in meta-inflammation, with a focus on their pathophysiologic roles in obesity, type 2 diabetes, dyslipidemia, and nonalcoholic steatohepatitis, and their potential therapeutic applications.
Collapse
Affiliation(s)
- Oscar Chávez-Talavera
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011 - EGID, F-59000 Lille, France
| | - Anne Tailleux
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011 - EGID, F-59000 Lille, France
| | - Philippe Lefebvre
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011 - EGID, F-59000 Lille, France
| | - Bart Staels
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011 - EGID, F-59000 Lille, France.
| |
Collapse
|
|
25
|
Jansen PLM, Ghallab A, Vartak N, Reif R, Schaap FG, Hampe J, Hengstler JG. The ascending pathophysiology of cholestatic liver disease. Hepatology 2017; 65:722-738. [PMID: 27981592 DOI: 10.1002/hep.28965] [Citation(s) in RCA: 218] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Revised: 10/26/2016] [Accepted: 11/17/2016] [Indexed: 02/06/2023]
Abstract
In this review we develop the argument that cholestatic liver diseases, particularly primary biliary cholangitis and primary sclerosing cholangitis (PSC), evolve over time with anatomically an ascending course of the disease process. The first and early lesions are in "downstream" bile ducts. This eventually leads to cholestasis, and this causes bile salt (BS)-mediated toxic injury of the "upstream" liver parenchyma. BS are toxic in high concentration. These concentrations are present in the canalicular network, bile ducts, and gallbladder. Leakage of bile from this network and ducts could be an important driver of toxicity. The liver has a great capacity to adapt to cholestasis, and this may contribute to a variable symptom-poor interval that is often observed. Current trials with drugs that target BS toxicity are effective in only about 50%-60% of primary biliary cholangitis patients, with no effective therapy in PSC. This motivated us to develop and propose a new view on the pathophysiology of primary biliary cholangitis and PSC in the hope that these new drugs can be used more effectively. These views may lead to better stratification of these diseases and to recommendations on a more "tailored" use of the new therapeutic agents that are currently tested in clinical trials. Apical sodium-dependent BS transporter inhibitors that reduce intestinal BS absorption lower the BS load and are best used in cholestatic patients. The effectiveness of BS synthesis-suppressing drugs, such as farnesoid X receptor agonists, is greatest when optimal adaptation is not yet established. By the time cytochrome P450 7A1 expression is reduced these drugs may be less effective. Anti-inflammatory agents are probably most effective in early disease, while drugs that antagonize BS toxicity, such as ursodeoxycholic acid and nor-ursodeoxycholic acid, may be effective at all disease stages. Endoscopic stenting in PSC should be reserved for situations of intercurrent cholestasis and cholangitis, not for cholestasis in end-stage disease. These are arguments to consider a step-wise pathophysiology for these diseases, with therapy adjusted to disease stage. An obstacle in such an approach is that disease stage-defining biomarkers are still lacking. This review is meant to serve as a call to prioritize the development of biomarkers that help to obtain a better stratification of these diseases. (Hepatology 2017;65:722-738).
Collapse
Affiliation(s)
- Peter L M Jansen
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.,Department of Surgery, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands.,Research Network of Liver Systems Medicine, Freiburg, Germany
| | - Ahmed Ghallab
- Research Network of Liver Systems Medicine, Freiburg, Germany.,Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany.,Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt
| | - Nachiket Vartak
- Research Network of Liver Systems Medicine, Freiburg, Germany.,Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany
| | - Raymond Reif
- Research Network of Liver Systems Medicine, Freiburg, Germany.,Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany
| | - Frank G Schaap
- Department of Surgery, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
| | - Jochen Hampe
- Research Network of Liver Systems Medicine, Freiburg, Germany.,Department of Medicine 1, Technical University Dresden, Dresden, Germany
| | - Jan G Hengstler
- Research Network of Liver Systems Medicine, Freiburg, Germany.,Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany
| |
Collapse
|
|
26
|
Lammert C, Vuppalanchi R. Future Therapies for Primary Sclerosing Cholangitis. PRIMARY SCLEROSING CHOLANGITIS 2017:153-166. [DOI: 10.1007/978-3-319-40908-5_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
|
27
|
Mousa HS, Carbone M, Malinverno F, Ronca V, Gershwin ME, Invernizzi P. Novel therapeutics for primary biliary cholangitis: Toward a disease-stage-based approach. Autoimmun Rev 2016; 15:870-876. [DOI: 10.1016/j.autrev.2016.07.003] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Accepted: 06/01/2016] [Indexed: 12/22/2022]
|
|
28
|
Halilbasic E, Fuchs C, Traussnigg S, Trauner M. Farnesoid X Receptor Agonists and Other Bile Acid Signaling Strategies for Treatment of Liver Disease. Dig Dis 2016; 34:580-8. [PMID: 27332721 DOI: 10.1159/000445268] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
The intracellular nuclear receptor farnesoid X receptor (FXR) and the transmembrane G protein-coupled receptor 5 (TGR5) respond to bile acids (BAs) by activating transcriptional networks and/or signaling cascades. These cascades affect the expression of a great number of target genes relevant for BA, cholesterol, lipid and carbohydrate metabolism, as well as genes involved in inflammation, fibrosis and carcinogenesis. FXR activation in the liver tissue and beyond, such as the gut-liver axis, kidney and adipose tissue, plays a role in metabolic diseases. These BA receptors activators hold promise to become a new class of drugs to be used in the treatment of chronic liver disease, hepatocellular cancer and extrahepatic inflammatory and metabolic diseases. This review discusses the relevant BA receptors, the new drugs that target BA transport and signaling and their possible applications.
Collapse
Affiliation(s)
- Emina Halilbasic
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | | | | | | |
Collapse
|
|
29
|
Abstract
Cholestatic liver diseases are hereditary or acquired disorders with impaired hepatic excretion and enterohepatic circulation of bile acids and other cholephiles. The distinct pathological mechanisms, particularly for the acquired forms of cholestasis, are not fully revealed, but advances in the understanding of the molecular mechanisms and identification of key regulatory mechanisms of the enterohepatic circulation of bile acids have unraveled common and central mechanisms, which can be pharmacologically targeted. This overview focuses on the central roles of farnesoid X receptor, fibroblast growth factor 19, and apical sodium-dependent bile acid transporter for the enterohepatic circulation of bile acids and their potential as new drug targets for the treatment of cholestatic liver disease.
Collapse
Affiliation(s)
- Martin Wagner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Wien, Austria
| |
Collapse
|
|
30
|
Wanek T, Halilbasic E, Visentin M, Mairinger S, Römermann K, Stieger B, Kuntner C, Müller M, Langer O, Trauner M. Influence of 24-Nor-Ursodeoxycholic Acid on Hepatic Disposition of [(18)F]Ciprofloxacin, a Positron Emission Tomography Study in Mice. J Pharm Sci 2016; 105:106-12. [PMID: 26852845 DOI: 10.1016/j.xphs.2015.11.014] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2015] [Revised: 10/28/2015] [Accepted: 11/05/2015] [Indexed: 01/10/2023]
Abstract
24-nor-ursodeoxycholic acid (norUDCA) is a novel therapeutic approach to cholestatic liver diseases. In mouse models of cholestasis, norUDCA induces basolateral multidrug resistance-associated proteins 4 (Mrp4) and 3 in hepatocytes, which provide alternative escape routes for bile acids accumulating during cholestasis but could also result in altered hepatic disposition of concomitantly administered substrate drugs. We used positron emission tomography imaging to study the influence of norUDCA on hepatic disposition of the model Mrp4 substrate [(18)F]ciprofloxacin in wild-type and Mdr2((-/-)) mice, a model of cholestasis. Animals underwent [(18)F]ciprofloxacin positron emission tomography at baseline and after norUDCA treatment. After norUDCA treatment, liver-to-blood area under the curve ratio of [(18)F]ciprofloxacin was significantly decreased compared to baseline, both in wild-type (-34.0 ± 2.1%) and Mdr2((-/-)) mice (-20.5 ± 6.0%). [(18)F]Ciprofloxacin uptake clearance from blood into liver was reduced by -17.1 ± 9.0% in wild-type and by -20.1 ± 7.3% in Mdr2((-/-)) mice. Real-time PCR analysis showed significant increases in hepatic Mrp4 and multidrug resistance-associated protein 3 mRNA after norUDCA. Transport experiments in organic anion transporting polypeptide (OATP)1B1-, OATP1B3-, and OATP2B1-transfected cells revealed weak transport of [(14)C]ciprofloxacin by OATP1B3 and OATP2B1 and no inhibition by norUDCA. In conclusion, our data suggest that changes in hepatic [(18)F]ciprofloxacin disposition in mice after norUDCA treatment were caused by induction of basolateral Mrp4 in hepatocytes.
Collapse
Affiliation(s)
- Thomas Wanek
- Biomedical Systems, Health and Environment Department, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria
| | - Emina Halilbasic
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Michele Visentin
- Department of Clinical Pharmacology and Toxicology, University Hospital, Zurich, Switzerland
| | - Severin Mairinger
- Biomedical Systems, Health and Environment Department, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria
| | - Kerstin Römermann
- Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine, Center for Systems Neuroscience, Hannover, Germany
| | - Bruno Stieger
- Department of Clinical Pharmacology and Toxicology, University Hospital, Zurich, Switzerland
| | - Claudia Kuntner
- Biomedical Systems, Health and Environment Department, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria
| | - Markus Müller
- Department of Clinical Pharmacology, Medical University of Vienna, Austria
| | - Oliver Langer
- Biomedical Systems, Health and Environment Department, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria; Department of Clinical Pharmacology, Medical University of Vienna, Austria.
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
| |
Collapse
|
|
31
|
Woolbright BL, Jaeschke H. Therapeutic targets for cholestatic liver injury. Expert Opin Ther Targets 2015; 20:463-75. [PMID: 26479335 DOI: 10.1517/14728222.2016.1103735] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Cholestasis is a reduction in bile flow that occurs during numerous pathologies. Blockage of the biliary tracts results in hepatic accumulation of bile acids or their conjugate bile salts. The molecular mechanisms behind liver injury associated with cholestasis are extensively studied, but not well understood. Multiple models of obstructive cholestasis result in a significant inflammatory infiltrate at the sites of necrosis that characterize the injury. AREAS COVERED This review will focus on direct bile acid toxicity during cholestasis, bile acid signaling processes and on the development and continuation of inflammation during cholestasis, with a focus on novel proposed molecular mediators of neutrophil recruitment. While significant progress has been made on these molecular mechanisms, a continued focus on how cholestasis and the innate immune system interact is necessary to discover targetable therapeutics that might protect the liver while leaving global immunity intact. EXPERT OPINION While bile acid toxicity likely occurs in humans and other mammals when toxic bile acids accumulate, persistent inflammation is likely responsible for continued liver injury during obstructive cholestasis. Targeting molecular mediators of inflammation may help prevent liver injury during acute cholestasis both in murine models and human patients.
Collapse
Affiliation(s)
- Benjamin L Woolbright
- a Department of Pharmacology , Toxicology & Therapeutics, University of Kansas Medical Center , 3901 Rainbow Blvd, MS 1018, Kansas City , KS , 66160 USA
| | - Hartmut Jaeschke
- a Department of Pharmacology , Toxicology & Therapeutics, University of Kansas Medical Center , 3901 Rainbow Blvd, MS 1018, Kansas City , KS , 66160 USA
| |
Collapse
|