|
1
|
Tatscher E, Mady S, Fickert P. Emerging Targets for the Treatment of Primary Sclerosing Cholangitis. Semin Liver Dis 2025. [PMID: 40418973 DOI: 10.1055/a-2601-9426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/28/2025]
Abstract
Primary sclerosing cholangitis (PSC) is a rare, progressive cholestatic disease of unknown etiology and characterized by inflammation and stricturing of intrahepatic and/or extrahepatic bile ducts. This process leads to bile duct scarring, progressive liver fibrosis, and end-stage liver disease. PSC is often associated with a specific form of inflammatory bowel disease and patients face a significant risk of developing cholangiocarcinoma and colorectal cancer. The clinical course of PSC can differ significantly between subtypes and affected individuals, representing a major obstacle to successful medical treatment trials. Numerous innovative therapeutic targets have been identified and, at least in part, explored, including nuclear and membrane receptors regulating bile acid metabolism and transport, modulation of gut microbiota, and signaling molecules involved in liver inflammation and fibrosis. Successful drug testing in preclinical PSC models as well as positive signals from some clinical studies justify hope. However, no medical treatment has so far been proven to improve transplant-free survival or overall survival in PSC patients. Disease-modifying drugs are urgently awaited. Despite ongoing efforts to improve study designs and implement treatment trials for novel drug targets, a central breakthrough has not yet been convincingly achieved. This situation might change in the near future. This article summarizes current research efforts aimed at developing medical treatments for PSC.
Collapse
Affiliation(s)
- Elisabeth Tatscher
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Samy Mady
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Peter Fickert
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| |
Collapse
|
|
2
|
Chen Y, Chen R, Li H, Shuai Z. Clinical management of autoimmune liver diseases: juncture, opportunities, and challenges ahead. Immunol Res 2025; 73:67. [PMID: 40195209 PMCID: PMC11976385 DOI: 10.1007/s12026-025-09622-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Accepted: 03/14/2025] [Indexed: 04/09/2025]
Abstract
The three major autoimmune liver diseases are autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC).These conditions are assumed to result from a breakdown in immunological tolerance, which leads to an inflammatory process that causes liver damage.The self-attack is started by T-helper cell-mediated identification of liver autoantigens and B-cell production of autoantibodies,and it is maintained by a reduction in the number and activity of regulatory T-cells.Infections and environmental factors have been explored as triggering factors for these conditions, in addition to a genetic predisposition.Allelic mutations in the HLA locus have been linked to vulnerability, as have relationships with single nucleotide polymorphisms in non-HLA genes.Despite the advances in the management of these diseases, there is no curative treatment for these disorders, and a significant number of patients eventually progress to an end-stage liver disease requiring liver transplantation.In this line, tailored immune-therapeutics have emerged as possible treatments to control the disease.In addition, early diagnosis and treatment are pivotal for reducing the long-lasting effects of these conditions and their burden on quality of life.Herein we present a review of the etiology, clinical presentation, diagnosis, and challenges on ALDs and the feasible solutions for these complex diseases.
Collapse
MESH Headings
- Humans
- Hepatitis, Autoimmune/therapy
- Hepatitis, Autoimmune/diagnosis
- Hepatitis, Autoimmune/immunology
- Hepatitis, Autoimmune/etiology
- Cholangitis, Sclerosing/therapy
- Cholangitis, Sclerosing/diagnosis
- Cholangitis, Sclerosing/immunology
- Liver Cirrhosis, Biliary/therapy
- Liver Cirrhosis, Biliary/diagnosis
- Liver Cirrhosis, Biliary/immunology
- Animals
- Immunotherapy/methods
- Autoimmune Diseases/therapy
- Autoimmune Diseases/diagnosis
- Disease Management
- Genetic Predisposition to Disease
Collapse
Affiliation(s)
- Yangfan Chen
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Ruofei Chen
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Haiyan Li
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Zongwen Shuai
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, 230032, China.
| |
Collapse
|
|
3
|
Sorrentino G. Microenvironmental control of the ductular reaction: balancing repair and disease progression. Cell Death Dis 2025; 16:246. [PMID: 40180915 PMCID: PMC11968979 DOI: 10.1038/s41419-025-07590-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 03/11/2025] [Accepted: 03/24/2025] [Indexed: 04/05/2025]
Abstract
The ductular reaction (DR) is a dynamic adaptive cellular response within the liver, triggered by various hepatic insults and characterized by an expansion of dysmorphic biliary epithelial cells and liver progenitors. This complex response presents a dual role, playing a pivotal function in liver regeneration but, paradoxically, contributing to the progression of liver diseases, depending upon specific contextual factors and signaling pathways involved. This comprehensive review aims to offer a holistic perspective on the DR, focusing into its intricate cellular and molecular mechanisms, highlighting its pathological significance, and exploring its potential therapeutic implications. An up-to-date understanding of the DR in the context of different liver injuries is provided, analyzing its contributions to liver regeneration, inflammation, fibrosis, and ultimately carcinogenesis. Moreover, the review highlights the role of multiple microenvironmental factors, including the influence of extracellular matrix, tissue mechanics and the interplay with the intricate hepatic cell ecosystem in shaping the DR's regulation. Finally, in vitro and in vivo experimental models of the DR will be discussed, providing insights into how researchers can study and manipulate this critical cellular response. By comprehensively addressing the multifaceted nature of the DR, this review contributes to a more profound understanding of its pathophysiological role in liver diseases, thus offering potential therapeutic avenues for hepatic disorders and improving patient outcomes.
Collapse
Affiliation(s)
- Giovanni Sorrentino
- Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy.
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy.
| |
Collapse
|
|
4
|
Manns MP, Bergquist A, Karlsen TH, Levy C, Muir AJ, Ponsioen C, Trauner M, Wong G, Younossi ZM. Primary sclerosing cholangitis. Nat Rev Dis Primers 2025; 11:17. [PMID: 40082445 DOI: 10.1038/s41572-025-00600-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/07/2025] [Indexed: 03/16/2025]
Abstract
Primary sclerosing cholangitis (PSC) is a chronic biliary inflammation associated with periductular fibrosis of the intrahepatic and extrahepatic bile ducts leading to strictures, bacterial cholangitis, decompensated liver disease and need for liver transplantation. This rare focal liver disease affects all races and ages, with a predominance of young males. There is an up to 88% association with inflammatory bowel disease. Although the aetiology is unknown and the pathophysiology is poorly understood, PSC is regarded as an autoimmune liver disease based on a strong immunogenetic background. Further, the associated risk for various malignancies, particularly cholangiocellular carcinoma, is also poorly understood. No medical therapy has been approved so far nor has been shown to improve transplant-free survival. However, ursodeoxycholic acid is widely used since it improves the biochemical parameters of cholestasis and is safe at low doses. MRI of the biliary tract is the primary imaging technology for diagnosis. Endoscopic interventions of the bile ducts should be limited to clinically relevant strictures for balloon dilatation, biopsy and brush cytology. End-stage liver disease with decompensation is an indication for liver transplantation with recurrent PSC in up to 38% of patients. Several novel therapeutic strategies are in various stages of development, including apical sodium-dependent bile acid transporter and ileal bile acid transporter inhibitors, integrin inhibitors, peroxisome proliferator-activated receptor agonists, CCL24 blockers, recombinant FGF19, CCR2/CCR5 inhibitors, farnesoid X receptor bile acid receptor agonists, and nor-ursodeoxycholic acid. Manipulation of the gut microbiome includes faecal microbiota transplantation. This article summarizes present knowledge and defines unmet medical needs to improve quality of life and survival.
Collapse
Affiliation(s)
- Michael P Manns
- Hannover Medical School (MHH) and Centre for Individualised Infection Medicine (CiiM), Hannover, Germany.
| | - Annika Bergquist
- Division of Hepatology, Department of Upper Gastrointestinal Disease, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
| | - Tom H Karlsen
- Norwegian PSC Research Center, Department of Transplantation Medicine, Clinic of Surgery and Specialized medicine, Oslo University Hospital, Oslo, Norway
- Research Institute of Internal Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Cynthia Levy
- Division of Digestive Health and Liver Diseases, University of Miami School of Medicine, Miami, FL, USA
| | - Andrew J Muir
- Division of Gastroenterology, Duke University School of Medicine, Durham, NC, USA
| | - Cyriel Ponsioen
- Department of Gastroenterology & Hepatology, Amsterdam University Medical Center, Amsterdam, The Netherlands
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Grace Wong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Union Hospital, Hong Kong SAR, China
| | | |
Collapse
|
|
5
|
Zhu C, Boucheron N, Al-Rubaye O, Chung BK, Thorbjørnsen LW, Köcher T, Schuster M, Claudel T, Halilbasic E, Kunczer V, Muscate F, Cavanagh LL, Waltenberger D, Lercher A, Ohradanova-Repic A, Schatzlmaier P, Stojakovic T, Scharnagl H, Bergthaler A, Stockinger H, Huber S, Bock C, Kenner L, Karlsen TH, Ellmeier W, Trauner M. 24-Nor-ursodeoxycholic acid improves intestinal inflammation by targeting T H17 pathogenicity and transdifferentiation. Gut 2025:gutjnl-2024-333297. [PMID: 40032499 DOI: 10.1136/gutjnl-2024-333297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Accepted: 01/28/2025] [Indexed: 03/05/2025]
Abstract
BACKGROUND 24-Nor-ursodeoxycholic acid (NorUDCA) is a novel therapeutic bile acid for treating immune-mediated cholestatic liver diseases, such as primary sclerosing cholangitis (PSC). OBJECTIVE Since PSC strongly associates with T helper-type-like 17 (TH17)-mediated intestinal inflammation, we explored NorUDCA's immunomodulatory potential on TH17 cells. DESIGN NorUDCA's impact on TH17 differentiation was assessed using a CD4+TNaive adoptive transfer mouse model, and on intraepithelial TH17 pathogenicity and transdifferentiation using an αCD3 stimulation model combined with interleukin-17A-fate-mapping. Mechanistic studies used molecular and multiomics approaches, flow cytometry and metabolic assays with pathogenic (p) TH17. Pathogenicity of pTH17 exposed to NorUDCA in vitro was evaluated following adoptive transfer in intestinal tissues or the central nervous system (CNS). Key findings were validated in an αCD3-stimulated humanised NSG mouse model reconstituted with peripheral blood mononuclear cells from patients with PSC. RESULTS NorUDCA suppressed TH17 effector function and enriched regulatory T cell (Treg) abundance upon CD4+TNaive cell transfer. NorUDCA mitigated intraepithelial TH17 pathogenicity and decreased the generation of proinflammatory 'TH1-like-TH17' cells, and enhanced TH17 transdifferentiation into Treg and Tr1 (regulatory type 1) cells in the αCD3-model. In vivo ablation revealed that Treg induction is crucial for NorUDCA's anti-inflammatory effect on TH17 pathogenicity. Mechanistically, NorUDCA restrained pTH17 effector function and simultaneously promoted functional Treg formation in vitro, by attenuating a glutamine-mTORC1-glycolysis signalling axis. Exposure of pTH17 to NorUDCA dampened their pathogenicity and expansion in the intestine or CNS upon transfer. NorUDCA's impact on TH17 inflammation was corroborated in the humanised NSG mouse model. CONCLUSION NorUDCA restricts TH17 inflammation in multiple mouse models, potentiating future clinical applications for treating TH17-mediated intestinal diseases and beyond.
Collapse
Affiliation(s)
- Ci Zhu
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Institute of Immunology, Center for Pathophysiology Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Nicole Boucheron
- Institute of Immunology, Center for Pathophysiology Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Osamah Al-Rubaye
- Institute of Immunology, Center for Pathophysiology Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Brian K Chung
- Department of Transplantation Medicine, Clinic of Surgery and Specialized Medicine, Oslo University Hospital and University of Oslo, Oslo, Norway
| | - Liv Wenche Thorbjørnsen
- Department of Transplantation Medicine, Clinic of Surgery and Specialized Medicine, Oslo University Hospital and University of Oslo, Oslo, Norway
| | - Thomas Köcher
- Vienna BioCenter Core Facilities, Metabolomics, Vienna BioCenter, Vienna, Austria
| | - Michael Schuster
- Biomedical Sequencing Facility, Cemm, Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Thierry Claudel
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Emina Halilbasic
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Victoria Kunczer
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Fanziska Muscate
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg Eppendorf, Hamburg, Germany
| | - Lois L Cavanagh
- Institute of Immunology, Center for Pathophysiology Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Darina Waltenberger
- Institute of Immunology, Center for Pathophysiology Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Alexander Lercher
- Cemm, Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Anna Ohradanova-Repic
- Institute for Hygiene and Applied Immunology, Center for Pathophysiology Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Philipp Schatzlmaier
- Institute for Hygiene and Applied Immunology, Center for Pathophysiology Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Tatjana Stojakovic
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, University Hospital Graz, Graz, Austria
| | - Hubert Scharnagl
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
| | - Andreas Bergthaler
- Cemm, Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
- Institute for Hygiene and Applied Immunology, Center for Pathophysiology Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Hannes Stockinger
- Institute for Hygiene and Applied Immunology, Center for Pathophysiology Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Samuel Huber
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christoph Bock
- Biomedical Sequencing Facility, Cemm, Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Lukas Kenner
- Division of Experimental and Translational Pathology, Department of Pathology, Medical University of Vienna, Vienna, Austria
- Unit of Laboratory Animal Pathology, Department for Pathobiology, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Tom H Karlsen
- Department of Transplantation Medicine, Clinic of Surgery and Specialized Medicine, Oslo University Hospital and University of Oslo, Oslo, Norway
| | - Wilfried Ellmeier
- Institute of Immunology, Center for Pathophysiology Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Michael Trauner
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| |
Collapse
|
|
6
|
Wu T, Wu J, Liu L, Song H. PDZK1 gene transfer ameliorates lipopolysaccharide-induced cholestasis in rats by rescuing hepatic ABC transporters. Biosci Biotechnol Biochem 2025; 89:390-397. [PMID: 39658368 DOI: 10.1093/bbb/zbae190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Accepted: 12/05/2024] [Indexed: 12/12/2024]
Abstract
Lipopolysaccharide (LPS) causes inflammatory cholestasis in sepsis. We investigated the role of PDZK1 in the repression of ABC transporters in LPS-induced cholestasis. Lentiviral gene transfer of PDZK1 to rats was conducted to explore its influence on cholestasis induced by LPS. And the effect of lentivirus-mediated shRNA targeting PDZK1 on ABC transporters in rat liver BRL-3A cells was evaluated. Lentiviral vector encoding rat PDZK1 was administered to rats by tail intravenous injection. Obviously elevated serum total bile acid level and liver biochemical markers in cholestatic rats were decreased by the Lv-PDZK1 delivery. Also, Lv-PDZK1 delivery stimulated the suppressed hepatic ABC transporters expression. In vitro, after the lentiviral vector LV3/PDZK1 shRNA transfection, no expression of PDZK1 and mild expression of ABC transporters were detected in BRL-3A cells by Western blotting. Our results indicate that the lentiviral-mediated hepatocyte PDZK1 expression ameliorates LPS-induced cholestasis in rats by rescuing hepatic ABC transporters expression.
Collapse
Affiliation(s)
- Tao Wu
- Central Laboratory, Department of Pharmacy, Wuhan Fourth Hospital, Wuhan, China
| | - Ji Wu
- Faculty of Medicine, Wuhan City College, Wuhan, China
| | - Li Liu
- Central Laboratory, Department of Pharmacy, Wuhan Fourth Hospital, Wuhan, China
| | - Hongping Song
- Central Laboratory, Department of Pharmacy, Wuhan Fourth Hospital, Wuhan, China
| |
Collapse
|
|
7
|
Fuchs CD, Simbrunner B, Baumgartner M, Campbell C, Reiberger T, Trauner M. Bile acid metabolism and signalling in liver disease. J Hepatol 2025; 82:134-153. [PMID: 39349254 DOI: 10.1016/j.jhep.2024.09.032] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 09/12/2024] [Accepted: 09/17/2024] [Indexed: 10/02/2024]
Abstract
Bile acids (BAs) serve as signalling molecules, efficiently regulating their own metabolism and transport, as well as key aspects of lipid and glucose homeostasis. BAs shape the gut microbial flora and conversely are metabolised by microbiota. Disruption of BA transport, metabolism and physiological signalling functions contribute to the pathogenesis and progression of a wide range of liver diseases including cholestatic disorders and MASLD (metabolic dysfunction-associated steatotic liver disease), as well as hepatocellular and cholangiocellular carcinoma. Additionally, impaired BA signalling may also affect the intestine and kidney, thereby contributing to failure of gut integrity and driving the progression and complications of portal hypertension, cholemic nephropathy and the development of extrahepatic malignancies such as colorectal cancer. In this review, we will summarise recent advances in the understanding of BA signalling, metabolism and transport, focusing on transcriptional regulation and novel BA-focused therapeutic strategies for cholestatic and metabolic liver diseases.
Collapse
Affiliation(s)
- Claudia D Fuchs
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Benedikt Simbrunner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Maximillian Baumgartner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Clarissa Campbell
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
| |
Collapse
|
|
8
|
Shijing T, Yinping P, Qiong Y, Deshuai L, Liancai Z, Jun T, Shaoyong L, Bochu W. Synthesis of TUDCA from chicken bile: immobilized dual-enzymatic system for producing artificial bear bile substitute. Microb Cell Fact 2024; 23:326. [PMID: 39623449 PMCID: PMC11613824 DOI: 10.1186/s12934-024-02592-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Accepted: 11/12/2024] [Indexed: 12/06/2024] Open
Abstract
Bear bile, a valuable animal-derived medicinal substance primarily composed of tauroursodeoxycholic acid (TUDCA), is widely distributed in the medicinal market across various countries due to its significant therapeutic potential. Given the extreme cruelty involved in bear bile extraction, researchers are focusing on developing synthetic bear bile powder as a more humane alternative. This review presents an industrially practical and environmentally friendly process for producing an artificial substitute for bear bile powder using inexpensive and readily available chicken bile powder through an immobilized 7α-,7β-HSDH dual-enzymatic syste. Current technology has facilitated the industrial production of TUDCA from Tauodeoxycholic acid (TCDCA) using chicken bile powder. The review begins by examining the chemical composition, structure, and properties of bear bile, followed by an outline of the pharmacological mechanisms and manufacturing methods of TUDCA, covering chemical synthesis and biotransformation methods, and a discussion on their respective advantages and disadvantages. Finally, the process of converting chicken bile powder into bear bile powder using an immobilized 7α-Hydroxysteroid Dehydrogenases(7α-HSDH) with 7β- Hydroxysteroid Dehydrogenases (7β-HSDH) dual-enzyme system is thoroughly explained. The main objective of this review is to propose a comprehensive strategy for the complete synthesis of artificial bear bile from chicken bile within a controlled laboratory setting.
Collapse
Affiliation(s)
- Tang Shijing
- Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, College of Bioengineering, Chongqing University, No. 174, Shapingba Main Street, Chongqing, 400030, People's Republic of China
| | - Pan Yinping
- Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, College of Bioengineering, Chongqing University, No. 174, Shapingba Main Street, Chongqing, 400030, People's Republic of China
| | - Yang Qiong
- Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, College of Bioengineering, Chongqing University, No. 174, Shapingba Main Street, Chongqing, 400030, People's Republic of China
| | - Lou Deshuai
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological & Chemical Engineering, Chongqing University of Education, Chongqing, 400067, People's Republic of China
| | - Zhu Liancai
- Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, College of Bioengineering, Chongqing University, No. 174, Shapingba Main Street, Chongqing, 400030, People's Republic of China.
| | - Tan Jun
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological & Chemical Engineering, Chongqing University of Education, Chongqing, 400067, People's Republic of China
| | - Liu Shaoyong
- Shanghai Kaibao Pharmaceutical Co., LTD., Shanghai, 200030, People's Republic of China
| | - Wang Bochu
- Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, College of Bioengineering, Chongqing University, No. 174, Shapingba Main Street, Chongqing, 400030, People's Republic of China.
| |
Collapse
|
|
9
|
Mehtani R, Rathi S. Recurrence of Primary Disease After Adult Liver Transplant - Risk Factors, Early Diagnosis, Management, and Prevention. J Clin Exp Hepatol 2024; 14:101432. [PMID: 38975605 PMCID: PMC11222954 DOI: 10.1016/j.jceh.2024.101432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Accepted: 04/14/2024] [Indexed: 07/09/2024] Open
Abstract
Liver transplantation offers a new lease of life to patients with end-stage liver disease and hepatocellular carcinoma. However, the implantation of an exogenous allograft and the accompanying immunosuppression bring their own challenges. Moreover, the persistence of risk factors for the initial liver insult place the new graft at a higher risk of damage. With the increasing number of liver transplants along with the improvement in survival posttransplant, the recurrence of primary disease in liver grafts has become more common. Pre-2015, the most common disease to recur after transplant was hepatitis C. However, directly acting antivirals have nearly eliminated this problem. The greatest challenge of disease recurrence we now face are those of nonalcoholic steatohepatitis, alcohol-related liver disease, and primary sclerosing cholangitis. We focus on the epidemiology and pathophysiology of the recurrence of primary disease after transplant. We also discuss means of early identification, risk stratification, prevention, and management of recurrent primary disease after liver transplantation.
Collapse
Affiliation(s)
- Rohit Mehtani
- Department of Hepatology, Amrita Institute of Medical Sciences and Research, Faridabad, Haryana, India
| | - Sahaj Rathi
- Department of Hepatology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| |
Collapse
|
|
10
|
Hof WFJ, de Boer JF, Verkade HJ. Emerging drugs for the treatment of progressive familial intrahepatic cholestasis: a focus on phase II and III trials. Expert Opin Emerg Drugs 2024; 29:305-320. [PMID: 38571480 DOI: 10.1080/14728214.2024.2336986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Accepted: 03/27/2024] [Indexed: 04/05/2024]
Abstract
INTRODUCTION Progressive familial intrahepatic cholestasis (PFIC) is a group of disorders characterized by inappropriate bile formation, causing hepatic accumulation of bile acids and, subsequently, liver injury. Until recently, no approved treatments were available for these patients. AREAS COVERED Recent clinical trials for PFIC treatment have focused on intestine-restricted ileal bile acid transporter (IBAT) inhibitors. These compounds aim to reduce the pool size of bile acids by interrupting their enterohepatic circulation. Other emerging treatments in the pipeline include systemic IBAT inhibitors, synthetic bile acid derivatives, compounds targeting bile acid synthesis via the FXR/FGF axis, and chaperones/potentiators that aim to enhance the residual activity of the mutated transporters. EXPERT OPINION Substantial progress has been made in drug development for PFIC patients during the last couple of years. Although data concerning long-term efficacy are as yet only scarcely available, new therapies have demonstrated robust efficacy in a considerable fraction of patients at least on the shorter term. However, a substantial fraction of PFIC patients do not respond to these novel therapies and thus still requires surgical treatment, including liver transplantation before adulthood. Hence, there is still an unmet medical need for long-term effective medical, preferably non-surgical, treatment for all PFIC patients.
Collapse
Affiliation(s)
- Willemien F J Hof
- Department of Pediatrics, University Medical Center Groningen, Groningen, The Netherlands
| | - Jan Freark de Boer
- Department of Pediatrics, University Medical Center Groningen, Groningen, The Netherlands
- Department of Laboratory Medicine, University Medical Center Groningen, Groningen, The Netherlands
| | - Henkjan J Verkade
- Department of Pediatrics, University Medical Center Groningen, Groningen, The Netherlands
| |
Collapse
|
|
11
|
Sohal A, Kowdley KV. Novel preclinical developments of the primary sclerosing cholangitis treatment landscape. Expert Opin Investig Drugs 2024; 33:335-345. [PMID: 38480008 DOI: 10.1080/13543784.2024.2330738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 03/11/2024] [Indexed: 03/19/2024]
Abstract
INTRODUCTION Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease associated with inflammation, fibrosis, and destruction of intra- and extrahepatic bile ducts. Despite substantial recent advances in our understanding of PSC, the only proven treatment of PSC is liver transplantation. There is an urgent unmet need to find medical therapies for this disorder. AREAS COVERED Multiple drugs are currently under evaluation as therapeutic options for this disease. This article summarizes the literature on the various novel therapeutic options that have been investigated and are currently under development for the treatment of PSC. EXPERT OPINION In the next decade, more than one drug will likely be approved for the treatment of the disease, and we will be looking at combination therapies for the optimal management of the disease.
Collapse
Affiliation(s)
- Aalam Sohal
- Department of Hepatology, Liver Institute Northwest, Seattle, USA
| | - Kris V Kowdley
- Department of Hepatology, Liver Institute Northwest, Seattle, USA
- Elson S. Floyd College of Medicine, Washington State University, Spokane, USA
| |
Collapse
|
|
12
|
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
|
|
13
|
Ye L, Ziesch A, Schneider JS, Ofner A, Nieß H, Denk G, Hohenester S, Mayr D, Mahajan UM, Munker S, Khaled NB, Wimmer R, Gerbes AL, Mayerle J, He Y, Geier A, Toni END, Zhang C, Reiter FP. The inhibition of YAP Signaling Prevents Chronic Biliary Fibrosis in the Abcb4 -/- Model by Modulation of Hepatic Stellate Cell and Bile Duct Epithelium Cell Pathophysiology. Aging Dis 2024; 15:338-356. [PMID: 37307826 PMCID: PMC10796084 DOI: 10.14336/ad.2023.0602] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Accepted: 06/02/2023] [Indexed: 06/14/2023] Open
Abstract
Primary sclerosing cholangitis (PSC) represents a chronic liver disease characterized by poor prognosis and lacking causal treatment options. Yes-associated protein (YAP) functions as a critical mediator of fibrogenesis; however, its therapeutic potential in chronic biliary diseases such as PSC remains unestablished. The objective of this study is to elucidate the possible significance of YAP inhibition in biliary fibrosis by examining the pathophysiology of hepatic stellate cells (HSC) and biliary epithelial cells (BEC). Human liver tissue samples from PSC patients were analyzed to assess the expression of YAP/connective tissue growth factor (CTGF) relative to non-fibrotic control samples. The pathophysiological relevance of YAP/CTGF in HSC and BEC was investigated in primary human HSC (phHSC), LX-2, H69, and TFK-1 cell lines through siRNA or pharmacological inhibition utilizing verteporfin (VP) and metformin (MF). The Abcb4-/- mouse model was employed to evaluate the protective effects of pharmacological YAP inhibition. Hanging droplet and 3D matrigel culture techniques were utilized to investigate YAP expression and activation status of phHSC under various physical conditions. YAP/CTGF upregulation was observed in PSC patients. Silencing YAP/CTGF led to inhibition of phHSC activation and reduced contractility of LX-2 cells, as well as suppression of epithelial-mesenchymal transition (EMT) in H69 cells and proliferation of TFK-1 cells. Pharmacological inhibition of YAP mitigated chronic liver fibrosis in vivo and diminished ductular reaction and EMT. YAP expression in phHSC was effectively modulated by altering extracellular stiffness, highlighting YAP's role as a mechanotransducer. In conclusion, YAP regulates the activation of HSC and EMT in BEC, thereby functioning as a checkpoint of fibrogenesis in chronic cholestasis. Both VP and MF demonstrate effectiveness as YAP inhibitors, capable of inhibiting biliary fibrosis. These findings suggest that VP and MF warrant further investigation as potential therapeutic options for the treatment of PSC.
Collapse
Affiliation(s)
- Liangtao Ye
- Digestive Diseases Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China.
- Department of Medicine II, University Hospital, LMU Munich, Germany.
| | - Andreas Ziesch
- Department of Medicine II, University Hospital, LMU Munich, Germany.
| | | | - Andrea Ofner
- Department of Medicine II, University Hospital, LMU Munich, Germany.
| | - Hanno Nieß
- Biobank of the Department of General, Visceral and Transplantion Surgery, University Hospital, LMU Munich, Germany.
| | - Gerald Denk
- Department of Medicine II, University Hospital, LMU Munich, Germany.
| | - Simon Hohenester
- Department of Medicine II, University Hospital, LMU Munich, Germany.
| | - Doris Mayr
- Institute of Pathology, Faculty of Medicine, LMU Munich, Germany.
| | - Ujjwal M. Mahajan
- Department of Medicine II, University Hospital, LMU Munich, Germany.
| | - Stefan Munker
- Department of Medicine II, University Hospital, LMU Munich, Germany.
| | - Najib Ben Khaled
- Department of Medicine II, University Hospital, LMU Munich, Germany.
| | - Ralf Wimmer
- Department of Medicine II, University Hospital, LMU Munich, Germany.
| | | | - Julia Mayerle
- Department of Medicine II, University Hospital, LMU Munich, Germany.
| | - Yulong He
- Digestive Diseases Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China.
| | - Andreas Geier
- Division of Hepatology, Department of Medicine II, University Hospital Würzburg, Würzburg, Germany.
| | - Enrico N. De Toni
- Department of Medicine II, University Hospital, LMU Munich, Germany.
| | - Changhua Zhang
- Digestive Diseases Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China.
| | - Florian P. Reiter
- Department of Medicine II, University Hospital, LMU Munich, Germany.
- Division of Hepatology, Department of Medicine II, University Hospital Würzburg, Würzburg, Germany.
| |
Collapse
|
|
14
|
Caligiuri A, Becatti M, Porro N, Borghi S, Marra F, Pastore M, Taddei N, Fiorillo C, Gentilini A. Oxidative Stress and Redox-Dependent Pathways in Cholangiocarcinoma. Antioxidants (Basel) 2023; 13:28. [PMID: 38247453 PMCID: PMC10812651 DOI: 10.3390/antiox13010028] [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: 10/30/2023] [Revised: 12/19/2023] [Accepted: 12/20/2023] [Indexed: 01/23/2024] Open
Abstract
Cholangiocarcinoma (CCA) is a primary liver tumor that accounts for 2% of all cancer-related deaths worldwide yearly. It can arise from cholangiocytes of biliary tracts, peribiliary glands, and possibly from progenitor cells or even hepatocytes. CCA is characterized by high chemoresistance, aggressiveness, and poor prognosis. Potentially curative surgical therapy is restricted to a small number of patients with early-stage disease (up to 35%). Accumulating evidence indicates that CCA is an oxidative stress-driven carcinoma resulting from chronic inflammation. Oxidative stress, due to enhanced reactive oxygen species (ROS) production and/or decreased antioxidants, has been recently suggested as a key factor in cholangiocyte oncogenesis through gene expression alterations and molecular damage. However, due to different experimental models and conditions, contradictory results regarding oxidative stress in cholangiocarcinoma have been reported. The role of ROS and antioxidants in cancer is controversial due to their context-dependent ability to stimulate tumorigenesis and support cancer cell proliferation or promote cell death. On these bases, the present narrative review is focused on illustrating the role of oxidative stress in cholangiocarcinoma and the main ROS-driven intracellular pathways. Heterogeneous data about antioxidant effects on cancer development are also discussed.
Collapse
Affiliation(s)
- Alessandra Caligiuri
- Department of Experimental and Clinical Medicine, University of Florence, 50139 Florence, Italy; (A.C.); (F.M.); (M.P.)
| | - Matteo Becatti
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50139 Florence, Italy; (M.B.); (N.P.); (S.B.); (N.T.)
| | - Nunzia Porro
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50139 Florence, Italy; (M.B.); (N.P.); (S.B.); (N.T.)
| | - Serena Borghi
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50139 Florence, Italy; (M.B.); (N.P.); (S.B.); (N.T.)
| | - Fabio Marra
- Department of Experimental and Clinical Medicine, University of Florence, 50139 Florence, Italy; (A.C.); (F.M.); (M.P.)
| | - Mirella Pastore
- Department of Experimental and Clinical Medicine, University of Florence, 50139 Florence, Italy; (A.C.); (F.M.); (M.P.)
| | - Niccolò Taddei
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50139 Florence, Italy; (M.B.); (N.P.); (S.B.); (N.T.)
| | - Claudia Fiorillo
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50139 Florence, Italy; (M.B.); (N.P.); (S.B.); (N.T.)
| | - Alessandra Gentilini
- Department of Experimental and Clinical Medicine, University of Florence, 50139 Florence, Italy; (A.C.); (F.M.); (M.P.)
| |
Collapse
|
|
15
|
Tan N, Lubel J, Kemp W, Roberts S, Majeed A. Current Therapeutics in Primary Sclerosing Cholangitis. J Clin Transl Hepatol 2023; 11:1267-1281. [PMID: 37577219 PMCID: PMC10412694 DOI: 10.14218/jcth.2022.00068s] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Revised: 01/01/2023] [Accepted: 01/20/2023] [Indexed: 07/03/2023] Open
Abstract
Primary sclerosing cholangitis (PSC) is an orphan, cholestatic liver disease that is characterized by inflammatory biliary strictures with variable progression to end-stage liver disease. Its pathophysiology is poorly understood. Chronic biliary inflammation is likely driven by immune dysregulation, gut dysbiosis, and environmental exposures resulting in gut-liver crosstalk and bile acid metabolism disturbances. There is no proven medical therapy that alters disease progression in PSC, with the commonly prescribed ursodeoxycholic acid being shown to improve liver biochemistry at low-moderate doses (15-23 mg/kg/day) but not alter transplant-free survival or liver-related outcomes. Liver transplantation is the only option for patients who develop end-stage liver disease or refractory complications of PSC. Immunosuppressive and antifibrotic agents have not proven to be effective, but there is promise for manipulation of the gut microbiome with fecal microbiota transplantation and antibiotics. Bile acid manipulation via alternate synthetic bile acids such as norursodeoxycholic acid, or interaction at a transcriptional level via nuclear receptor agonists and fibrates have shown potential in phase II trials in PSC with several leading to larger phase III trials. In view of the enhanced malignancy risk, statins, and aspirin show potential for reducing the risk of colorectal cancer and cholangiocarcinoma in PSC patients. For patients who develop clinically relevant strictures with cholestatic symptoms and worsening liver function, balloon dilatation is safer compared with biliary stent insertion with equivalent clinical efficacy.
Collapse
Affiliation(s)
- Natassia Tan
- Department of Gastroenterology and Hepatology, Alfred Health; Central Clinical School, Monash University, Melbourne, Australia
| | - John Lubel
- Department of Gastroenterology and Hepatology, Alfred Health; Central Clinical School, Monash University, Melbourne, Australia
| | - William Kemp
- Department of Gastroenterology and Hepatology, Alfred Health; Central Clinical School, Monash University, Melbourne, Australia
| | - Stuart Roberts
- Department of Gastroenterology and Hepatology, Alfred Health; Central Clinical School, Monash University, Melbourne, Australia
| | - Ammar Majeed
- Department of Gastroenterology and Hepatology, Alfred Health; Central Clinical School, Monash University, Melbourne, Australia
| |
Collapse
|
|
16
|
Truong JK, Li J, Li Q, Pachura K, Rao A, Gumber S, Fuchs CD, Feranchak AP, Karpen SJ, Trauner M, Dawson PA. Active enterohepatic cycling is not required for the choleretic actions of 24-norUrsodeoxycholic acid in mice. JCI Insight 2023; 8:e149360. [PMID: 36787187 PMCID: PMC10070106 DOI: 10.1172/jci.insight.149360] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Accepted: 02/07/2023] [Indexed: 02/15/2023] Open
Abstract
The pronounced choleretic properties of 24-norUrsodeoxycholic acid (norUDCA) to induce bicarbonate-rich bile secretion have been attributed to its ability to undergo cholehepatic shunting. The goal of this study was to identify the mechanisms underlying the choleretic actions of norUDCA and the role of the bile acid transporters. Here, we show that the apical sodium-dependent bile acid transporter (ASBT), organic solute transporter-α (OSTα), and organic anion transporting polypeptide 1a/1b (OATP1a/1b) transporters are dispensable for the norUDCA stimulation of bile flow and biliary bicarbonate secretion. Chloride channels in biliary epithelial cells provide the driving force for biliary secretion. In mouse large cholangiocytes, norUDCA potently stimulated chloride currents that were blocked by siRNA silencing and pharmacological inhibition of calcium-activated chloride channel transmembrane member 16A (TMEM16A) but unaffected by ASBT inhibition. In agreement, blocking intestinal bile acid reabsorption by coadministration of an ASBT inhibitor or bile acid sequestrant did not impact norUDCA stimulation of bile flow in WT mice. The results indicate that these major bile acid transporters are not directly involved in the absorption, cholehepatic shunting, or choleretic actions of norUDCA. Additionally, the findings support further investigation of the therapeutic synergy between norUDCA and ASBT inhibitors or bile acid sequestrants for cholestatic liver disease.
Collapse
Affiliation(s)
- Jennifer K. Truong
- Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Emory University School of Medicine, Children’s Healthcare of Atlanta, Atlanta, Georgia, USA
| | - Jianing Li
- Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Emory University School of Medicine, Children’s Healthcare of Atlanta, Atlanta, Georgia, USA
| | - Qin Li
- Department of Pediatrics, University of Pittsburgh Medical Center Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Kimberly Pachura
- Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Emory University School of Medicine, Children’s Healthcare of Atlanta, Atlanta, Georgia, USA
| | - Anuradha Rao
- Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Emory University School of Medicine, Children’s Healthcare of Atlanta, Atlanta, Georgia, USA
| | - Sanjeev Gumber
- Division of Pathology and Laboratory Medicine, Yerkes National Research Center, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Claudia Daniela Fuchs
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Andrew P. Feranchak
- Department of Pediatrics, University of Pittsburgh Medical Center Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Saul J. Karpen
- Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Emory University School of Medicine, Children’s Healthcare of Atlanta, Atlanta, Georgia, USA
| | - Michael Trauner
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Paul A. Dawson
- Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Emory University School of Medicine, Children’s Healthcare of Atlanta, Atlanta, Georgia, USA
| |
Collapse
|
|
17
|
Nevens F, Trauner M, Manns MP. Primary biliary cholangitis as a roadmap for the development of novel treatments for cholestatic liver diseases †. J Hepatol 2023; 78:430-441. [PMID: 36272496 DOI: 10.1016/j.jhep.2022.10.007] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 10/07/2022] [Accepted: 10/07/2022] [Indexed: 11/16/2022]
Abstract
The discovery of nuclear receptors and transporters has contributed to the development of new drugs for the treatment of cholestatic liver diseases. Particular progress has been made in the development of second-line therapies for PBC. These new drugs can be separated into compounds primarily targeting cholestasis, molecules targeting fibrogenesis and molecules with immune-mediated action. Finally, drugs aimed at symptom relief (pruritus and fatigue) are also under investigation. Obeticholic acid is currently the only approved second-line therapy for PBC. Drugs in the late phase of clinical development include peroxisome proliferator-activated receptor agonists, norursodeoxycholic acid and NADPH oxidase 1/4 inhibitors.
Collapse
Affiliation(s)
- Frederik Nevens
- Department of Gastroenterology and Hepatology, University Hospital KU Leuven, Belgium; Centre of ERN RARE-LIVER.
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Austria; Centre of ERN RARE-LIVER
| | - Michael P Manns
- Hannover Medical School, Hannover, Germany; Centre of ERN RARE-LIVER
| |
Collapse
|
|
18
|
Gee LMV, Barron-Millar B, Leslie J, Richardson C, Zaki MYW, Luli S, Burgoyne RA, Cameron RIT, Smith GR, Brain JG, Innes B, Jopson L, Dyson JK, McKay KRC, Pechlivanis A, Holmes E, Berlinguer-Palmini R, Victorelli S, Mells GF, Sandford RN, Palmer J, Kirby JA, Kiourtis C, Mokochinski J, Hall Z, Bird TG, Borthwick LA, Morris CM, Hanson PS, Jurk D, Stoll EA, LeBeau FEN, Jones DEJ, Oakley F. Anti-Cholestatic Therapy with Obeticholic Acid Improves Short-Term Memory in Bile Duct-Ligated Mice. THE AMERICAN JOURNAL OF PATHOLOGY 2023; 193:11-26. [PMID: 36243043 DOI: 10.1016/j.ajpath.2022.09.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 09/03/2022] [Accepted: 09/28/2022] [Indexed: 12/12/2022]
Abstract
Patients with cholestatic liver disease, including those with primary biliary cholangitis, can experience symptoms of impaired cognition or brain fog. This phenomenon remains unexplained and is currently untreatable. Bile duct ligation (BDL) is an established rodent model of cholestasis. In addition to liver changes, BDL animals develop cognitive symptoms early in the disease process (before development of cirrhosis and/or liver failure). The cellular mechanisms underpinning these cognitive symptoms are poorly understood. Herein, the study explored the neurocognitive symptom manifestations, and tested potential therapies, in BDL mice, and used human neuronal cell cultures to explore translatability to humans. BDL animals exhibited short-term memory loss and showed reduced astrocyte coverage of the blood-brain barrier, destabilized hippocampal network activity, and neuronal senescence. Ursodeoxycholic acid (first-line therapy for most human cholestatic diseases) did not reverse symptomatic or mechanistic aspects. In contrast, obeticholic acid (OCA), a farnesoid X receptor agonist and second-line anti-cholestatic agent, normalized memory function, suppressed blood-brain barrier changes, prevented hippocampal network deficits, and reversed neuronal senescence. Co-culture of human neuronal cells with either BDL or human cholestatic patient serum induced cellular senescence and increased mitochondrial respiration, changes that were limited again by OCA. These findings provide new insights into the mechanism of cognitive symptoms in BDL animals, suggesting that OCA therapy or farnesoid X receptor agonism could be used to limit cholestasis-induced neuronal senescence.
Collapse
Affiliation(s)
- Lucy M V Gee
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Ben Barron-Millar
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Jack Leslie
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Claire Richardson
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Marco Y W Zaki
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom; Biochemistry Department, Faculty of Pharmacy, Minia University, Minia, Egypt
| | - Saimir Luli
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Rachel A Burgoyne
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Rainie I T Cameron
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Graham R Smith
- Bioinformatics Support Unit, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - John G Brain
- Liver Unit, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom; Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Barbara Innes
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Laura Jopson
- Liver Unit, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
| | - Jessica K Dyson
- Liver Unit, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
| | - Katherine R C McKay
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Alexandros Pechlivanis
- Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - Elaine Holmes
- Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, United Kingdom
| | | | - Stella Victorelli
- Department of Physiology and Biomedical Engineering, Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota
| | - George F Mells
- Academic Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom
| | - Richard N Sandford
- Academic Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom
| | - Jeremy Palmer
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - John A Kirby
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | | | - Joao Mokochinski
- MRC London Institute of Medical Sciences, London, United Kingdom
| | - Zoe Hall
- Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, Hammersmith Hospital Campus, London, United Kingdom
| | - Thomas G Bird
- Cancer Research UK Beatson Institute, Glasgow, United Kingdom; MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - Lee A Borthwick
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Christopher M Morris
- Medical Toxicology Centre, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Peter S Hanson
- Medical Toxicology Centre, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Diana Jurk
- Department of Physiology and Biomedical Engineering, Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota
| | | | - Fiona E N LeBeau
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - David E J Jones
- Liver Unit, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom; Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Fiona Oakley
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
| |
Collapse
|
|
19
|
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
|
|
20
|
Owen A, Patten D, Vigneswara V, Frampton J, Newsome PN. PDGFRα/Sca-1 Sorted Mesenchymal Stromal Cells Reduce Liver Injury in Murine Models of Hepatic Ischemia-Reperfusion Injury. Stem Cells 2022; 40:1056-1070. [PMID: 35999023 PMCID: PMC9707286 DOI: 10.1093/stmcls/sxac059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 07/06/2022] [Indexed: 11/12/2022]
Abstract
Liver transplantation is an effective therapy, but increasing demand for donor organs has led to the use of marginal donor organs with increased complication rates. Mesenchymal stromal cells (MSC) pleiotropically modulate aberrant immune-mediated responses and represent a potential therapy to target the inflammation seen post-transplant with marginal donor livers. To avoid the confounding effects of xenotransplantation seen in studies with human MSC, a PDGFRα/Sca-1 (PaS) sorted MSC population was used which was analogous to human MSC populations (LNGFR+Thy-1+VCAM-1Hi). PaS MSC are a well-described population that demonstrate MSC properties without evidence of clonal mutation during expansion. We demonstrate their anti-inflammatory properties herein through their suppression of T-lymphocyte proliferation in vitro and secretion of anti-inflammatory cytokines (IL-10 and OPG) after stimulation (P = .004 and P = .003). The MDR2-/- model of biliary injury and hepatic ischemia-reperfusion (HIR) injury models were used to replicate the non-anastomotic biliary complications seen following liver transplantation. Systemic MSC therapy in MDR2-/- mice led to reduced liver injury with an increase in restorative macrophages (5913 ± 333.9 vs 12 597 ± 665.8, P = .002, n = 7) and a change in lymphocyte ratios (3.55 ± 0.37 vs 2.59 ± 0.139, P = .023, n = 17), whereas subcutaneous administration of MSC showed no beneficial effect. MSC also reduced cell death in the HIR model assessed by Periodic acid-Schiff (PAS) staining (91.7% ± 2.8 vs 80.1% ± 4.6, P = .03). Systemically administered quantum dot-labeled MSC were tracked using single-cell resolution CryoViz imaging which demonstrated their sequestration in the lungs alongside retention/redistribution to injured liver tissue. MSC represent a potential novel therapy in marginal organ transplantation which warrants further study.
Collapse
Affiliation(s)
| | | | | | | | - Philip N Newsome
- Corresponding author: Philip N. Newsome, Centre for Liver and Gastrointestinal Research, Institute of Biomedical Research, University of Birmingham, Vincent Drive, Birmingham B15 2TT, UK.
| |
Collapse
|
|
21
|
Panzitt K, Zollner G, Marschall HU, Wagner M. Recent advances on FXR-targeting therapeutics. Mol Cell Endocrinol 2022; 552:111678. [PMID: 35605722 DOI: 10.1016/j.mce.2022.111678] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Revised: 04/25/2022] [Accepted: 04/27/2022] [Indexed: 12/25/2022]
Abstract
The bile acid receptor FXR has emerged as a bona fide drug target for chronic cholestatic and metabolic liver diseases, ahead of all non-alcoholic fatty liver disease (NAFLD). FXR is highly expressed in the liver and intestine and activation at both sites differentially contributes to its desired metabolic effects. Unrestricted FXR activation, however, also comes along with undesired effects such as a pro-atherogenic lipid profile, pruritus and hepatocellular toxicity under certain conditions. Several pre-clinical studies have confirmed the potency of FXR activation for cholestatic and metabolic liver diseases, but overall it remains still open whether selective activation of intestinal FXR is advantageous over pan-FXR activation and whether restricted or modulated FXR activation can limit some of the side effects. Even more, FXR antagonist also bear the potential as intestinal-selective drugs in NAFLD models. In this review we will discuss the molecular prerequisites for FXR activation, pan-FXR activation and intestinal FXR in/activation from a therapeutic point of view, different steroidal and non-steroidal FXR agonists, ways to restrict FXR activation and finally what we have learned from pre-clinical models and clinical trials with different FXR therapeutics.
Collapse
Affiliation(s)
- Katrin Panzitt
- Research Unit for Translational Nuclear Receptor Research, Medical University Graz, Graz, Austria; Division of Gastroenterology and Hepatology, Medical University Graz, Graz, Austria
| | - Gernot Zollner
- Division of Gastroenterology and Hepatology, Medical University Graz, Graz, Austria
| | - Hanns-Ulrich Marschall
- Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Martin Wagner
- Research Unit for Translational Nuclear Receptor Research, Medical University Graz, Graz, Austria; Division of Gastroenterology and Hepatology, Medical University Graz, Graz, Austria.
| |
Collapse
|
|
22
|
Yang R, Du C, Cao T, Wang G, Jiang X, Gao J, Lin T, Sun C, Ding R, Tian W, Chen H. Synthesis and Anti-Hepatoma Activities of U12 Derivatives Arresting G0/G1 Phase and Inducing Apoptosis by PI3K/AKT/mTOR Pathway. Pharmaceuticals (Basel) 2022; 15:ph15010107. [PMID: 35056164 PMCID: PMC8781819 DOI: 10.3390/ph15010107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 01/12/2022] [Accepted: 01/14/2022] [Indexed: 11/22/2022] Open
Abstract
Ursodeoxycholic acid (UDCA) is a first-line clinical drug for the treatment of liver diseases. U12, a derivative of UDCA, showed effective anti-hepatoma activities in previous works. However, the low polarity and large doses limited the druglikeness of U12. In this study, the structural modification and optimization of U12 were further investigated and twelve U12 derivatives were synthesized by substitution, esterification and amidation reactions. The evaluation of the cytotoxicity of synthetic derivatives against hepatoma cell lines (HepG2) indicated that U12-I, U12a-d and U12h showed more effective cytotoxic effects on the growth of HepG2 cells than U12, and the preliminary structure–activity relationship was discussed. Among them, U12a exhibited the most potent anti-hepatocellular carcinoma activity. Mechanism studies indicated that U12a inhibited HepG2 cell proliferation by arresting the G0/G1 phase, and suppressed the activation of the PI3K/AKT/mTOR pathway. Further studies showed that U12a induced HepG2 cells apoptosis through activating the caspase signaling pathway. Furthermore, U12a evidently inhibits the growth of HepG2-derived tumor xenografts in vivo without observable adverse effects. Thus, U12a might be considered as a promising candidate for the treatment of hepatocellular carcinoma.
Collapse
|
|
23
|
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]
|
|
24
|
Abstract
Cholestatic and non-alcoholic fatty liver disease (NAFLD) share several key pathophysiological mechanisms which can be targeted by novel therapeutic concepts that are currently developed for both areas. Nuclear receptors (NRs) are ligand-activated transcriptional regulators of key metabolic processes including hepatic lipid and glucose metabolism, energy expenditure and bile acid (BA) homoeostasis, as well as inflammation, fibrosis and cellular proliferation. Dysregulation of these processes contributes to the pathogenesis and progression of cholestatic as well as fatty liver disease, placing NRs at the forefront of novel therapeutic approaches. This includes BA and fatty acid activated NRs such as farnesoid-X receptor (FXR) and peroxisome proliferator-activated receptors, respectively, for which high affinity therapeutic ligands targeting specific or multiple isoforms have been developed. Moreover, novel liver-specific ligands for thyroid hormone receptor beta 1 complete the spectrum of currently available NR-targeted drugs. Apart from FXR ligands, BA signalling can be targeted by mimetics of FXR-activated fibroblast growth factor 19, modulation of their enterohepatic circulation through uptake inhibitors in hepatocytes and enterocytes, as well as novel BA derivatives undergoing cholehepatic shunting (instead of enterohepatic circulation). Other therapeutic approaches more directly target inflammation and/or fibrosis as critical events of disease progression. Combination strategies synergistically targeting metabolic disturbances, inflammation and fibrosis may be ultimately necessary for successful treatment of these complex and multifactorial disorders.
Collapse
Affiliation(s)
- Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Claudia Daniela Fuchs
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| |
Collapse
|
|
25
|
Bile Acid Dysregulation Is Intrinsically Related to Cachexia in Tumor-Bearing Mice. Cancers (Basel) 2021; 13:cancers13246389. [PMID: 34945009 PMCID: PMC8699129 DOI: 10.3390/cancers13246389] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 12/03/2021] [Accepted: 12/14/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Cancer cachexia is considered a multi-organ syndrome. An improved understanding of how circulating molecules can affect tissues and mediate their crosstalk in the pathogenesis of cancer cachexia is emerging. Considering the various actions of bile acids on host metabolism and immunity, they could represent innovative targets in cancer cachexia. In this study, we investigated how bile acids could contribute to this syndrome by assessing the bile flow, by comparing the impact on bile acid pathways of cachexia-inducing and non-cachexia-inducing cell sublines, and by investigating the effects of ursodeoxycholic acid, a choleretic compound, in cachectic mice. Altogether, our analyses strengthen the importance of bile acids and their receptors as key players in the metabolic disorders associated with cancer, thereby laying the foundation for new therapeutic opportunities. Abstract Bile acids exert diverse actions on host metabolism and immunity through bile acid-activated receptors, including Takeda G protein-coupled receptor 5 (TGR5). We have recently evidenced an alteration in bile acids in cancer cachexia, an inflammatory and metabolic syndrome contributing to cancer death. This current study aims to further explore the links emerging between bile acids and cancer cachexia. First, we showed that bile flow is reduced in cachectic mice. Next, comparing mice inoculated with cachexia-inducing and with non-cachexia-inducing C26 colon carcinoma cells, we demonstrated that alterations in the bile acid pathways and profile are directly associated with cachexia. Finally, we performed an interventional study using ursodeoxycholic acid (UDCA), a compound commonly used in hepatobiliary disorders, to induce bile acid secretion and decrease inflammation. We found that UDCA does not improve hepatic inflammation and worsens muscle atrophy in cachectic mice. This exacerbation of the cachectic phenotype upon UDCA was accompanied by a decreased TGR5 activity, suggesting that TGR5 agonists, known to reduce inflammation in several pathological conditions, could potentially counteract cachectic features. This work brings to light major evidence sustaining the emerging links between bile acids and cancer cachexia and reinforces the interest in studying bile acid-activated receptors in this context.
Collapse
|
|
26
|
Abbas N, Quraishi MN, Trivedi P. Emerging drugs for the treatment of primary sclerosing cholangitis. Curr Opin Pharmacol 2021; 62:23-35. [PMID: 34894541 DOI: 10.1016/j.coph.2021.11.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 11/02/2021] [Accepted: 11/07/2021] [Indexed: 12/11/2022]
Abstract
Primary sclerosing cholangitis (PSC) is a rare immune-mediated cholestatic disease for which no medical therapy has been shown to slow disease progression. Consequently, liver transplantation is the only lifesaving intervention for patients, and despite being a rare disease, PSC is the lead indication for transplantation across several European countries. The vast majority of patients (>70%) also develop inflammatory bowel disease (IBD) at some point in their lifetime, which imparts added lifetime risks of hepatobiliary malignancy and colorectal cancer. The rare disease nature, variable and often slow rates of disease progression (years rather than months), and lack of robust surrogate biomarkers for early stage yet high risk disease, represent critical challenges in trial design that have long precluded the development of effective medical treatment. However, the horizon for new treatments is encouraging, given innovative clinical trial programmes led by industry, alongside several investigator-initiated studies. Herein, we outline the current platform of interventional trials in PSC, before discussing emerging areas of therapeutic interest.
Collapse
Affiliation(s)
- Nadir Abbas
- Liver Unit, University Hospitals Birmingham Queen Elizabeth, Birmingham, UK; NIHR Birmingham Biomedical Research Centre, Centre for Liver and Gastroenterology Research, University of Birmingham, UK; Institute of Immunology and Immunotherapy, University of Birmingham, UK
| | - Mohammad Nabil Quraishi
- Department of Gastroenterology, University Hospital Birmingham NHS Trust, UK; University of Birmingham Microbiome Treatment Centre, University of Birmingham, UK
| | - Palak Trivedi
- Liver Unit, University Hospitals Birmingham Queen Elizabeth, Birmingham, UK; NIHR Birmingham Biomedical Research Centre, Centre for Liver and Gastroenterology Research, University of Birmingham, UK; Institute of Immunology and Immunotherapy, University of Birmingham, UK.
| |
Collapse
|
|
27
|
Abstract
Cholestatic jaundice is a common presenting feature of hepatobiliary and/or metabolic dysfunction in the newborn and young infant. Timely detection of cholestasis, followed by rapid step-wise evaluation to determine the etiology, is crucial to identify those causes that are amenable to medical or surgical intervention and to optimize outcomes for all infants. In the past 2 decades, genetic etiologies have been elucidated for many cholestatic diseases, and next-generation sequencing, whole-exome sequencing, and whole-genome sequencing now allow for relatively rapid and cost-effective diagnosis of conditions not previously identifiable via standard blood tests and/or liver biopsy. Advances have also been made in our understanding of risk factors for parenteral nutrition-associated cholestasis/liver disease. New lipid emulsion formulations, coupled with preventive measures to decrease central line-associated bloodstream infections, have resulted in lower rates of cholestasis and liver disease in infants and children receiving long-term parental nutrition. Unfortunately, little progress has been made in determining the exact cause of biliary atresia. The median age at the time of the hepatoportoenterostomy procedure is still greater than 60 days; consequently, biliary atresia remains the primary indication for pediatric liver transplantation. Several emerging therapies may reduce the bile acid load to the liver and improve outcomes in some neonatal cholestatic disorders. The goal of this article is to review the etiologies, diagnostic algorithms, and current and future management strategies for infants with cholestasis.
Collapse
Affiliation(s)
- Amy G Feldman
- Digestive Health Institute, Children's Hospital Colorado, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, CO
| | - Ronald J Sokol
- Digestive Health Institute, Children's Hospital Colorado, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, CO
| |
Collapse
|
|
28
|
Floreani A, De Martin S. Treatment of primary sclerosing cholangitis. Dig Liver Dis 2021; 53:1531-1538. [PMID: 34011480 DOI: 10.1016/j.dld.2021.04.028] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 04/16/2021] [Accepted: 04/21/2021] [Indexed: 02/06/2023]
Abstract
Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by progressive fibro-stenotic strictures and destruction of the biliary tree. Currently, there is no effective treatment which can delay its progression or ameliorate the transplant-free survival. Moreover, a major chontroversy in PSC is whether to use UDCA. More recently, novel pharmacological agents emerged aiming at: i) modulation of bile composition; ii) immunomodulation; iii) targeting the gut microbiome; iv) targeting fibrosis. Successful PSC therapy, however, will be most likely a personalized combination of different drugs plus endoscopic treatment. This review aims at offering an overview on the experimental pharmacological strategies currently exploited for PSC treatment.
Collapse
Affiliation(s)
- Annarosa Floreani
- Scientific Consultant, Scientific Institute for Research, Hospitalization and Healthcare, Negrar, Verona, Italy; Senior Scholar, University of Padova, Padova, Italy.
| | - Sara De Martin
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Italy
| |
Collapse
|
|
29
|
Zhu C, Boucheron N, Müller AC, Májek P, Claudel T, Halilbasic E, Baazim H, Lercher A, Viczenczova C, Hainberger D, Preglej T, Sandner L, Alteneder M, Gülich AF, Khan M, Hamminger P, Remetic J, Ohradanova-Repic A, Schatzlmaier P, Donner C, Fuchs CD, Stojakovic T, Scharnagl H, Sakaguchi S, Weichhart T, Bergthaler A, Stockinger H, Ellmeier W, Trauner M. 24-Norursodeoxycholic acid reshapes immunometabolism in CD8 + T cells and alleviates hepatic inflammation. J Hepatol 2021; 75:1164-1176. [PMID: 34242699 PMCID: PMC8522806 DOI: 10.1016/j.jhep.2021.06.036] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2020] [Revised: 06/15/2021] [Accepted: 06/17/2021] [Indexed: 01/12/2023]
Abstract
BACKGROUND & AIMS 24-Norursodeoxycholic acid (NorUDCA) is a novel therapeutic bile acid used to treat immune-mediated cholestatic liver diseases, such as primary sclerosing cholangitis (PSC), where dysregulated T cells including CD8+ T cells contribute to hepatobiliary immunopathology. We hypothesized that NorUDCA may directly modulate CD8+ T cell function thus contributing to its therapeutic efficacy. METHODS NorUDCA's immunomodulatory effects were first studied in Mdr2-/- mice, as a cholestatic model of PSC. To differentiate NorUDCA's immunomodulatory effects on CD8+ T cell function from its anticholestatic actions, we also used a non-cholestatic model of hepatic injury induced by an excessive CD8+ T cell immune response upon acute non-cytolytic lymphocytic choriomeningitis virus (LCMV) infection. Studies included molecular and biochemical approaches, flow cytometry and metabolic assays in murine CD8+ T cells in vitro. Mass spectrometry was used to identify potential CD8+ T cell targets modulated by NorUDCA. The signaling effects of NorUDCA observed in murine cells were validated in circulating T cells from patients with PSC. RESULTS NorUDCA demonstrated immunomodulatory effects by reducing hepatic innate and adaptive immune cells, including CD8+ T cells in the Mdr2-/- model. In the non-cholestatic model of CD8+ T cell-driven immunopathology induced by acute LCMV infection, NorUDCA ameliorated hepatic injury and systemic inflammation. Mechanistically, NorUDCA demonstrated strong immunomodulatory efficacy in CD8+ T cells affecting lymphoblastogenesis, expansion, glycolysis and mTORC1 signaling. Mass spectrometry identified that NorUDCA regulates CD8+ T cells by targeting mTORC1. NorUDCA's impact on mTORC1 signaling was further confirmed in circulating PSC CD8+ T cells. CONCLUSIONS NorUDCA has a direct modulatory impact on CD8+ T cells and attenuates excessive CD8+ T cell-driven hepatic immunopathology. These findings are relevant for treatment of immune-mediated liver diseases such as PSC. LAY SUMMARY Elucidating the mechanisms by which 24-norursodeoxycholic acid (NorUDCA) works for the treatment of immune-mediated liver diseases, such as primary sclerosing cholangitis, is of considerable clinical interest. Herein, we uncovered an unrecognized property of NorUDCA in the immunometabolic regulation of CD8+ T cells, which has therapeutic relevance for immune-mediated liver diseases, including PSC.
Collapse
Affiliation(s)
- Ci Zhu
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria,Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Nicole Boucheron
- Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
| | - André C. Müller
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Peter Májek
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Thierry Claudel
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Emina Halilbasic
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Hatoon Baazim
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Alexander Lercher
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Csilla Viczenczova
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Daniela Hainberger
- Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Teresa Preglej
- Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Lisa Sandner
- Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Marlis Alteneder
- Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Alexandra F. Gülich
- Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Matarr Khan
- Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Patricia Hamminger
- Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Jelena Remetic
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Anna Ohradanova-Repic
- Institute for Hygiene and Applied Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Philipp Schatzlmaier
- Institute for Hygiene and Applied Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Clemens Donner
- Institute for Hygiene and Applied Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Claudia D. Fuchs
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Tatjana Stojakovic
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, University Hospital Graz, Graz, Austria
| | - Hubert Scharnagl
- Clinical Institute of Medical and Chemical Laboratory of Diagnostics, Medical University of Graz, Graz, Austria
| | - Shinya Sakaguchi
- Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Thomas Weichhart
- Institute of Medical Genetics, Center of Pathobiochemistry and Genetics, Medical University of Vienna, Vienna, Austria
| | - Andreas Bergthaler
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Hannes Stockinger
- Institute for Hygiene and Applied Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Wilfried Ellmeier
- Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Michael Trauner
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
| |
Collapse
|
|
30
|
Involvement of Autophagy in Ageing and Chronic Cholestatic Diseases. Cells 2021; 10:cells10102772. [PMID: 34685751 PMCID: PMC8534511 DOI: 10.3390/cells10102772] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 10/05/2021] [Accepted: 10/13/2021] [Indexed: 01/18/2023] Open
Abstract
Autophagy is a “housekeeping” lysosomal degradation process involved in numerous physiological and pathological processes in all eukaryotic cells. The dysregulation of hepatic autophagy has been described in several conditions, from obesity to diabetes and cholestatic disease. We review the role of autophagy, focusing on age-related cholestatic diseases, and discuss its therapeutic potential and the molecular targets identified to date. The accumulation of toxic BAs is the main cause of cell damage in cholestasis patients. BAs and their receptor, FXR, have been implicated in the regulation of hepatic autophagy. The mechanisms by which cholestasis induces liver damage include mitochondrial dysfunction, oxidative stress and ER stress, which lead to cell death and ultimately to liver fibrosis as a compensatory mechanism to reduce the damage. The stimulation of autophagy seems to ameliorate the liver damage. Autophagic activity decreases with age in several species, whereas its basic extends lifespan in animals, suggesting that it is one of the convergent mechanisms of several longevity pathways. No strategies aimed at inducing autophagy have yet been tested in cholestasis patients. However, its stimulation can be viewed as a novel therapeutic strategy that may reduce ageing-dependent liver deterioration and also mitigate hepatic steatosis.
Collapse
|
|
31
|
Reich M, Spomer L, Klindt C, Fuchs K, Stindt J, Deutschmann K, Höhne J, Liaskou E, Hov JR, Karlsen TH, Beuers U, Verheij J, Ferreira-Gonzalez S, Hirschfield G, Forbes SJ, Schramm C, Esposito I, Nierhoff D, Fickert P, Fuchs CD, Trauner M, García-Beccaria M, Gabernet G, Nahnsen S, Mallm JP, Vogel M, Schoonjans K, Lautwein T, Köhrer K, Häussinger D, Luedde T, Heikenwalder M, Keitel V. Downregulation of TGR5 (GPBAR1) in biliary epithelial cells contributes to the pathogenesis of sclerosing cholangitis. J Hepatol 2021; 75:634-646. [PMID: 33872692 DOI: 10.1016/j.jhep.2021.03.029] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 03/24/2021] [Accepted: 03/25/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Primary sclerosing cholangitis (PSC) is characterized by chronic inflammation and progressive fibrosis of the biliary tree. The bile acid receptor TGR5 (GPBAR1) is found on biliary epithelial cells (BECs), where it promotes secretion, proliferation and tight junction integrity. Thus, we speculated that changes in TGR5-expression in BECs may contribute to PSC pathogenesis. METHODS TGR5-expression and -localization were analyzed in PSC livers and liver tissue, isolated bile ducts and BECs from Abcb4-/-, Abcb4-/-/Tgr5Tg and ursodeoxycholic acid (UDCA)- or 24-norursodeoxycholic acid (norUDCA)-fed Abcb4-/- mice. The effects of IL8/IL8 homologues on TGR5 mRNA and protein levels were studied. BEC gene expression was analyzed by single-cell transcriptomics (scRNA-seq) from distinct mouse models. RESULTS TGR5 mRNA expression and immunofluorescence staining intensity were reduced in BECs of PSC and Abcb4-/- livers, in Abcb4-/- extrahepatic bile ducts, but not in intrahepatic macrophages. No changes in TGR5 BEC fluorescence intensity were detected in liver tissue of other liver diseases, including primary biliary cholangitis. Incubation of BECs with IL8/IL8 homologues, but not with other cytokines, reduced TGR5 mRNA and protein levels. BECs from Abcb4-/- mice had lower levels of phosphorylated Erk and higher expression levels of Icam1, Vcam1 and Tgfβ2. Overexpression of Tgr5 abolished the activated inflammatory phenotype characteristic of Abcb4-/- BECs. NorUDCA-feeding restored TGR5-expression levels in BECs in Abcb4-/- livers. CONCLUSIONS Reduced TGR5 levels in BECs from patients with PSC and Abcb4-/- mice promote development of a reactive BEC phenotype, aggravate biliary injury and thus contribute to the pathogenesis of sclerosing cholangitis. Restoration of biliary TGR5-expression levels represents a previously unknown mechanism of action of norUDCA. LAY SUMMARY Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease-associated with progressive inflammation of the bile duct, leading to fibrosis and end-stage liver disease. Bile acid (BA) toxicity may contribute to the development and disease progression of PSC. TGR5 is a membrane-bound receptor for BAs, which is found on bile ducts and protects bile ducts from BA toxicity. In this study, we show that TGR5 levels were reduced in bile ducts from PSC livers and in bile ducts from a genetic mouse model of PSC. Our investigations indicate that lower levels of TGR5 in bile ducts may contribute to PSC development and progression. Furthermore, treatment with norUDCA, a drug currently being tested in a phase III trial for PSC, restored TGR5 levels in biliary epithelial cells.
Collapse
Affiliation(s)
- Maria Reich
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany
| | - Lina Spomer
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany
| | - Caroline Klindt
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany
| | - Katharina Fuchs
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany
| | - Jan Stindt
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany
| | - Kathleen Deutschmann
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany
| | - Johanna Höhne
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany
| | - Evaggelia Liaskou
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK; NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Johannes R Hov
- Norwegian PSC Research Centre and Section of Gastroenterology at the Department of Transplantation Medicine, and Research Institute of Internal Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Tom H Karlsen
- Norwegian PSC Research Centre and Section of Gastroenterology at the Department of Transplantation Medicine, and Research Institute of Internal Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Ulrich Beuers
- Department of Gastroenterology and Hepatology and Tytgat Institute for Liver and Intestinal Research and Department of Pathology, Amsterdam University Medical Centers, Location AMC, AGEM Amsterdam, The Netherlands
| | - Joanne Verheij
- Department of Gastroenterology and Hepatology and Tytgat Institute for Liver and Intestinal Research and Department of Pathology, Amsterdam University Medical Centers, Location AMC, AGEM Amsterdam, The Netherlands
| | | | - Gideon Hirschfield
- Toronto Centre for Liver Disease, Toronto General Hospital, Toronto, Canada
| | - Stuart J Forbes
- Centre for Regenerative Medicine, University of Edinburgh, UK
| | - Christoph Schramm
- I. Department of Medicine and Martin Zeitz Centre for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Irene Esposito
- Institute of Pathology, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany
| | - Dirk Nierhoff
- Department of Gastroenterology and Hepatology, University of Cologne, Cologne, Germany
| | - Peter Fickert
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Claudia Daniela Fuchs
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Michael Trauner
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - María García-Beccaria
- Division of Chronic Inflammation and Cancer, German Cancer Research Center Heidelberg (DKFZ), Heidelberg, Germany
| | - Gisela Gabernet
- Quantitative Biology Center (QBiC), Eberhard-Karls University of Tübingen, Tübingen, Germany
| | - Sven Nahnsen
- Quantitative Biology Center (QBiC), Eberhard-Karls University of Tübingen, Tübingen, Germany
| | - Jan-Philipp Mallm
- Single Cell Open Lab, German Cancer Research Center Heidelberg (DKFZ), Heidelberg, Germany
| | - Marina Vogel
- DKFZ Genomics and Proteomics Core Facility, German Cancer Research Center Heidelberg (DKFZ), Heidelberg, Germany
| | - Kristina Schoonjans
- Laboratory of Metabolic Signaling, Institute of Bioengineering, School of Life Sciences and School of Engineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Tobias Lautwein
- Genomics and Transcriptomics Laboratory, Biologisch-Medizinisches-Forschungszentrum (BMFZ), Heinrich Heine University Düsseldorf, Germany
| | - Karl Köhrer
- Genomics and Transcriptomics Laboratory, Biologisch-Medizinisches-Forschungszentrum (BMFZ), Heinrich Heine University Düsseldorf, Germany
| | - Dieter Häussinger
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany
| | - Tom Luedde
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany
| | - Mathias Heikenwalder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center Heidelberg (DKFZ), Heidelberg, Germany
| | - Verena Keitel
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany.
| |
Collapse
|
|
32
|
Bergström Å, Gerling M, Van Hul N, Fernández Moro C, Rozell B, Toftgård R, Sur I. Severe liver disease resembling PSC in mice with K5-Cre mediated deletion of Krüppel-like factor 5 (Klf5). Transgenic Res 2021; 30:701-707. [PMID: 34117597 PMCID: PMC8478727 DOI: 10.1007/s11248-021-00267-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 06/06/2021] [Indexed: 11/30/2022]
Abstract
Chronic cholestatic liver diseases including primary sclerosing cholangitis (PSC) present a complex spectrum with regards to the cause, age of manifestation and histopathological features. Current treatment options are severely limited primarily due to a paucity of model systems mirroring the disease. Here, we describe the Keratin 5 (K5)-Cre; Klf5fl/fl mouse that spontaneously develops severe liver disease during the postnatal period with features resembling PSC including a prominent ductular reaction, fibrotic obliteration of the bile ducts and secondary degeneration/necrosis of liver parenchyma. Over time, there is an expansion of Sox9+ hepatocytes in the damaged livers suggestive of a hepatocyte-mediated regenerative response. We conclude that Klf5 is required for the normal function of the hepatobiliary system and that the K5-Cre; Klf5fl/fl mouse is an excellent model to probe the molecular events interlinking damage and regenerative response in the liver.
Collapse
Affiliation(s)
- Åsa Bergström
- Department of Biosciences and Nutrition, Karolinska Institutet, 141 83, Huddinge, Sweden
| | - Marco Gerling
- Department of Biosciences and Nutrition, Karolinska Institutet, 141 83, Huddinge, Sweden
- Tema Cancer, Karolinska University Hospital, 171 76, Stockholm, Sweden
| | - Noémi Van Hul
- Department of Cell and Molecular Biology, Karolinska Institutet, 171 77, Stockholm, Sweden
| | - Carlos Fernández Moro
- Department Clinical Pathology and Cancer Diagnostics, Karolinska University Hospital, 141 86, Stockholm, Sweden
- Department of Laboratory Medicine, Karolinska Institutet, 141 52, Huddinge, Sweden
| | - Björn Rozell
- Department of Laboratory Medicine, Karolinska Institutet, 141 52, Huddinge, Sweden
| | - Rune Toftgård
- Department of Biosciences and Nutrition, Karolinska Institutet, 141 83, Huddinge, Sweden
| | - Inderpreet Sur
- Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77, Stockholm, Sweden.
| |
Collapse
|
|
33
|
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
|
|
34
|
McCain JD, Chascsa DM, Lindor KD. Assessing and managing symptom burden and quality of life in primary sclerosing cholangitis patients. Expert Opin Orphan Drugs 2021. [DOI: 10.1080/21678707.2021.1898370] [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: 12/24/2022]
Affiliation(s)
- Josiah D. McCain
- Department of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, Arizona, USA
| | - David M. Chascsa
- Department of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, Arizona, USA
- Department of Transplant Center, Mayo Clinic, Phoenix, Arizona, USA
| | - Keith D. Lindor
- Office of University Provost, Arizona State University, Arizona, USA
| |
Collapse
|
|
35
|
Neonatale Cholestase. Monatsschr Kinderheilkd 2021. [DOI: 10.1007/s00112-020-01042-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
|
|
36
|
Gao RY, Shearn CT, Orlicky DJ, Battista KD, Alexeev EE, Cartwright IM, Lanis JM, Kostelecky RE, Ju C, Colgan SP, Fennimore BP. Bile acids modulate colonic MAdCAM-1 expression in a murine model of combined cholestasis and colitis. Mucosal Immunol 2021; 14:479-490. [PMID: 33004979 PMCID: PMC7954872 DOI: 10.1038/s41385-020-00347-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Accepted: 09/02/2020] [Indexed: 02/07/2023]
Abstract
Primary sclerosing cholangitis (PSC) is a progressive fibrosing cholestatic liver disease that is strongly associated with inflammatory bowel disease (IBD). PSC-associated IBD (PSC-IBD) displays a unique phenotype characterized by right-side predominant colon inflammation and increased risk of colorectal cancer compared to non-PSC-IBD. The frequent association and unique phenotype of PSC-IBD suggest distinctive underlying disease mechanisms from other chronic liver diseases or IBD alone. Multidrug resistance protein 2 knockout (Mdr2-/-) mice develop spontaneous cholestatic liver injury and fibrosis mirroring human PSC. As a novel model of PSC-IBD, we treated Mdr2-/- mice with dextran sulfate sodium (DSS) to chemically induce colitis (Mdr2-/-/DSS). Mdr2-/- mice demonstrate alterations in fecal bile acid composition and enhanced colitis susceptibility with increased colonic adhesion molecule expression, particularly mucosal addressin-cell adhesion molecule 1 (MAdCAM-1). In vitro, ursodeoxycholic acid (UDCA) co-treatment resulted in a dose dependent attenuation of TNF-α-induced endothelial MAdCAM-1 expression. In the combined Mdr2-/-/DSS model, UDCA supplementation attenuated colitis severity and downregulated intestinal MAdCAM-1 expression. These findings suggest a potential mechanistic role for alterations in bile acid signaling in modulating MAdCAM-1 expression and colitis susceptibility in cholestasis-associated colitis. Together, our findings provide a novel model and new insight into the pathogenesis and potential treatment of PSC-IBD.
Collapse
Affiliation(s)
- Rachel Y Gao
- Department of Medicine and the Mucosal Inflammation Program, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Colin T Shearn
- Department of Pediatrics Division of Pediatric Gastroenterology, Hepatology and Nutrition, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - David J Orlicky
- Department of Pathology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Kayla D Battista
- Department of Medicine and the Mucosal Inflammation Program, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Erica E Alexeev
- Department of Medicine and the Mucosal Inflammation Program, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Ian M Cartwright
- Department of Medicine and the Mucosal Inflammation Program, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, CO, USA
| | - Jordi M Lanis
- Department of Medicine and the Mucosal Inflammation Program, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Rachael E Kostelecky
- Department of Medicine and the Mucosal Inflammation Program, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Cynthia Ju
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Sean P Colgan
- Department of Medicine and the Mucosal Inflammation Program, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, CO, USA
| | - Blair P Fennimore
- Department of Medicine and the Mucosal Inflammation Program, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
| |
Collapse
|
|
37
|
Seelig A. P-Glycoprotein: One Mechanism, Many Tasks and the Consequences for Pharmacotherapy of Cancers. Front Oncol 2020; 10:576559. [PMID: 33194688 PMCID: PMC7649427 DOI: 10.3389/fonc.2020.576559] [Citation(s) in RCA: 121] [Impact Index Per Article: 24.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Accepted: 08/31/2020] [Indexed: 12/31/2022] Open
Abstract
P-glycoprotein or multidrug resistance protein (MDR1) is an adenosine triphosphate (ATP) binding cassette transporter (ABCB1) intensely investigated because it is an obstacle to successful pharmacotherapy of cancers. P-glycoprotein prevents cellular uptake of a large number of structurally and functionally diverse compounds, including most cancer therapeutics and in this way causes multidrug resistance (MDR). To overcome MDR, and thus improve cancer treatment, an understanding of P-glycoprotein inhibition at the molecular level is required. With this goal in mind, we propose rules that predict whether a compound is a modulator, substrate, inhibitor, or inducer of P-glycoprotein. This new set of rules is derived from a quantitative analysis of the drug binding and transport properties of P-glycoprotein. We further discuss the role of P-glycoprotein in immune surveillance and cell metabolism. Finally, the predictive power of the proposed rules is demonstrated with a set of FDA approved drugs which have been repurposed for cancer therapy.
Collapse
Affiliation(s)
- Anna Seelig
- Biozentrum, University of Basel, Basel, Switzerland
| |
Collapse
|
|
38
|
Sahu R, Mishra R, Majee C. An insight into primary biliary cholangitis and its recent advances in treatment: semi-synthetic analogs to combat ursodeoxycholic-acid resistance. Expert Rev Gastroenterol Hepatol 2020; 14:985-998. [PMID: 32674617 DOI: 10.1080/17474124.2020.1797485] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
INTRODUCTION Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease which on progression causes cirrhosis; various studies also suggested that several diseases can co-exist in patients. In existing depiction of disease PBC, apart from entire use of ursodeoxycholic acid (UDCA), several patients need to step forward to liver-transplantation or death due to resistance or non-responder with UDCA monotherapy. AREAS COVERED To overcome this non-respondent treatment, novel bile acid semi-synthetic analogs have been identified which shows their potency against for farnesoid X receptor and transmembrane G protein-coupled receptor-5 which are identified as target for many developing analogs which have desirable pharmacokinetic profiles. EXPERT OPINION A range of studies suggests that adding semisynthetic analogs in therapeutic regime improves liver biochemistries in patients with suboptimal response to UDCA. Thus, the aspire of this review is to abridge and compare therapeutic value and current markets affirm of various bile acids semi-synthetic analogs which certainly are having promising effects in PBC monotherapy or in pooled treatment with UDCA for PBC.
Collapse
Affiliation(s)
- Rakesh Sahu
- Department of Pharmaceutical Chemistry, Noida Institute of Engineering and Technology (Pharmacy Institute) , Greater Noida, India
| | - Rakhi Mishra
- Department of Pharmaceutical Chemistry, Noida Institute of Engineering and Technology (Pharmacy Institute) , Greater Noida, India
| | - Chandana Majee
- Department of Pharmaceutical Chemistry, Noida Institute of Engineering and Technology (Pharmacy Institute) , Greater Noida, India
| |
Collapse
|
|
39
|
Gabás‐Rivera C, Jurado‐Ruiz E, Sánchez‐Ortiz A, Romanos E, Martínez‐Beamonte R, Navarro MA, Surra JC, Arnal C, Rodríguez‐Yoldi MJ, Andrés‐Lacueva C, Osada J. Dietary Squalene Induces CytochromesCyp2b10andCyp2c55Independently of Sex, Dose, and Diet in Several Mouse Models. Mol Nutr Food Res 2020; 64:e2000354. [DOI: 10.1002/mnfr.202000354] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Affiliation(s)
- Clara Gabás‐Rivera
- Departamento Bioquímica y Biología Molecular y Celular Facultad de Veterinaria Instituto de Investigación Sanitaria de Aragón (IISA) Universidad de Zaragoza Zaragoza 50013 Spain
- CIBER de Fisiopatología de la Obesidad y Nutrición (CIBEROBN) Instituto de Salud Carlos III Madrid 28029 Spain
| | | | | | - Eduardo Romanos
- Instituto de Investigación Sanitaria de Aragón (IISA) Universidad de Zaragoza Zaragoza 50009 Spain
| | - Roberto Martínez‐Beamonte
- Departamento Bioquímica y Biología Molecular y Celular Facultad de Veterinaria Instituto de Investigación Sanitaria de Aragón (IISA) Universidad de Zaragoza Zaragoza 50013 Spain
- Instituto Agroalimentario de Aragón CITA‐Universidad de Zaragoza Zaragoza 50013 Spain
- CIBER de Fisiopatología de la Obesidad y Nutrición (CIBEROBN) Instituto de Salud Carlos III Madrid 28029 Spain
| | - María A. Navarro
- Departamento Bioquímica y Biología Molecular y Celular Facultad de Veterinaria Instituto de Investigación Sanitaria de Aragón (IISA) Universidad de Zaragoza Zaragoza 50013 Spain
- Instituto Agroalimentario de Aragón CITA‐Universidad de Zaragoza Zaragoza 50013 Spain
- CIBER de Fisiopatología de la Obesidad y Nutrición (CIBEROBN) Instituto de Salud Carlos III Madrid 28029 Spain
| | - Joaquín C. Surra
- Instituto Agroalimentario de Aragón CITA‐Universidad de Zaragoza Zaragoza 50013 Spain
- Departamento de Producción Animal Instituto de Investigación Sanitaria de Aragón (IISA) Escuela Politécnica Superior de Huesca Huesca 22071 Spain
- CIBER de Fisiopatología de la Obesidad y Nutrición (CIBEROBN) Instituto de Salud Carlos III Madrid 28029 Spain
| | - Carmen Arnal
- Instituto Agroalimentario de Aragón CITA‐Universidad de Zaragoza Zaragoza 50013 Spain
- Departamento de Patología Animal Facultad de Veterinaria Instituto de Investigación Sanitaria de Aragón (IISA) Universidad de Zaragoza Zaragoza 50013 Spain
- CIBER de Fisiopatología de la Obesidad y Nutrición (CIBEROBN) Instituto de Salud Carlos III Madrid 28029 Spain
| | - María J. Rodríguez‐Yoldi
- Instituto Agroalimentario de Aragón CITA‐Universidad de Zaragoza Zaragoza 50013 Spain
- Departamento de Farmacología y Fisiología Instituto de Investigación Sanitaria de Aragón (IISA) Facultad de Veterinaria Universidad de Zaragoza Zaragoza 50013 Spain
- CIBER de Fisiopatología de la Obesidad y Nutrición (CIBEROBN) Instituto de Salud Carlos III Madrid 28029 Spain
| | - Cristina Andrés‐Lacueva
- Biomarkers and Nutrimetabolomics Laboratory Department of Nutrition Food Sciences and Gastronomy Faculty of Pharmacy and Food Sciences University of Barcelona Barcelona 08028 Spain
- CIBER de Fragilidad y Envejecimiento Saludable (CIBERFES) Instituto de Salud Carlos III Madrid 28029 Spain
| | - Jesús Osada
- Departamento Bioquímica y Biología Molecular y Celular Facultad de Veterinaria Instituto de Investigación Sanitaria de Aragón (IISA) Universidad de Zaragoza Zaragoza 50013 Spain
- Instituto Agroalimentario de Aragón CITA‐Universidad de Zaragoza Zaragoza 50013 Spain
- CIBER de Fisiopatología de la Obesidad y Nutrición (CIBEROBN) Instituto de Salud Carlos III Madrid 28029 Spain
| |
Collapse
|
|
40
|
Dropmann A, Dooley S, Dewidar B, Hammad S, Dediulia T, Werle J, Hartwig V, Ghafoory S, Woelfl S, Korhonen H, Janicot M, Wosikowski K, Itzel T, Teufel A, Schuppan D, Stojanovic A, Cerwenka A, Nittka S, Piiper A, Gaiser T, Beraza N, Milkiewicz M, Milkiewicz P, Brain JG, Jones DEJ, Weiss TS, Zanger UM, Ebert M, Meindl-Beinker NM. TGF-β2 silencing to target biliary-derived liver diseases. Gut 2020; 69:1677-1690. [PMID: 31992593 PMCID: PMC7456737 DOI: 10.1136/gutjnl-2019-319091] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Revised: 12/16/2019] [Accepted: 12/17/2019] [Indexed: 12/13/2022]
Abstract
OBJECTIVE TGF-β2 (TGF-β, transforming growth factor beta), the less-investigated sibling of TGF-β1, is deregulated in rodent and human liver diseases. Former data from bile duct ligated and MDR2 knockout (KO) mouse models for human cholestatic liver disease suggested an involvement of TGF-β2 in biliary-derived liver diseases. DESIGN As we also found upregulated TGFB2 in liver tissue of patients with primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), we now fathomed the positive prospects of targeting TGF-β2 in early stage biliary liver disease using the MDR2-KO mice. Specifically, the influence of TgfB2 silencing on the fibrotic and inflammatory niche was analysed on molecular, cellular and tissue levels. RESULTS TgfB2-induced expression of fibrotic genes in cholangiocytes and hepatic stellate cellswas detected. TgfB2 expression in MDR2-KO mice was blunted using TgfB2-directed antisense oligonucleotides (AON). Upon AON treatment, reduced collagen deposition, hydroxyproline content and αSMA expression as well as induced PparG expression reflected a significant reduction of fibrogenesis without adverse effects on healthy livers. Expression analyses of fibrotic and inflammatory genes revealed AON-specific regulatory effects on Ccl3, Ccl4, Ccl5, Mki67 and Notch3 expression. Further, AON treatment of MDR2-KO mice increased tissue infiltration by F4/80-positive cells including eosinophils, whereas the number of CD45-positive inflammatory cells decreased. In line, TGFB2 and CD45 expression correlated positively in PSC/PBC patients and localised in similar areas of the diseased liver tissue. CONCLUSIONS Taken together, our data suggest a new mechanistic explanation for amelioration of fibrogenesis by TGF-β2 silencing and provide a direct rationale for TGF-β2-directed drug development.
Collapse
Affiliation(s)
- Anne Dropmann
- Molecular Hepatology-Alcohol Associated Diseases, Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Steven Dooley
- Molecular Hepatology-Alcohol Associated Diseases, Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Bedair Dewidar
- Molecular Hepatology-Alcohol Associated Diseases, Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt
| | - Seddik Hammad
- Molecular Hepatology-Alcohol Associated Diseases, Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt
| | - Tatjana Dediulia
- Molecular Hepatology-Alcohol Associated Diseases, Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Julia Werle
- Molecular Hepatology-Alcohol Associated Diseases, Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Vanessa Hartwig
- Molecular Hepatology-Alcohol Associated Diseases, Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Shahrouz Ghafoory
- Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Heidelberg, Germany
| | - Stefan Woelfl
- Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Heidelberg, Germany
| | | | | | | | - Timo Itzel
- Hepatology and Clinical Bioinformatics, Department of Medicine II, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Andreas Teufel
- Hepatology and Clinical Bioinformatics, Department of Medicine II, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Detlef Schuppan
- Research Center for Immunotherapy, University Medical Center, Johannes Gutenberg University, Mainz, Germany
- Institute of Translational Immunology, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Ana Stojanovic
- Department of Immunobiochemistry, Centre for Biomedicine and Medical Technology (CBTM) and European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Adelheid Cerwenka
- Department of Immunobiochemistry, Centre for Biomedicine and Medical Technology (CBTM) and European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Stefanie Nittka
- Institute for Clinical Chemistry, Medical Faculty Mannheim of the University of Heidelberg, University Hospital Mannheim, Mannheim, Germany
| | - Albrecht Piiper
- Medizinische Klinik 1, Klinikum der Goethe-Universität, Frankfurt am Main, Germany
| | - Timo Gaiser
- Institute of Pathology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Naiara Beraza
- Gut Microbes and Health Institute Strategic Programme, Quadram Institute, Norwich, UK
- CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Derio, Spain
| | | | - Piotr Milkiewicz
- Liver and Internal Medicine Unit, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - John G Brain
- NIHR Applied Immunobiology and Transplant Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
| | - David E J Jones
- NIHR Applied Immunobiology and Transplant Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
| | - Thomas S Weiss
- Department of Pediatrics and Juvenile Medicine, Center for Liver Cell Research, University of Regensburg Hospital, Regensburg, Germany
| | - Ulrich M Zanger
- Department of Molecular and Cell Biology, Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany
- Eberhard-Karls-University Tübingen, Tübingen, Germany
| | - Matthias Ebert
- Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Nadja M Meindl-Beinker
- Molecular Hepatology-Alcohol Associated Diseases, Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| |
Collapse
|
|
41
|
Abstract
Neonatal cholestasis is characterized by conjugated hyperbilirubinemia in the newborn and young infant and is a sign common to over 100 hepatobiliary and/or metabolic disorders. A timely evaluation for its etiology is critical in order to quickly identify treatable causes such as biliary atresia, many of which benefit from early therapy. An expanding group of molecularly defined disorders involving bile formation, canalicular transporters, tight junction proteins and inborn errors of metabolism are being continuously discovered because of advances in genetic testing and bioinformatics. The advent of next generation sequencing has transformed our ability to test for multiple genes and whole exome or whole genome sequencing within days to weeks, enabling rapid and affordable molecular diagnosis for disorders that cannot be directly diagnosed from standard blood tests or liver biopsy. Thus, our diagnostic algorithms for neonatal cholestasis are undergoing transformation, moving genetic sequencing to earlier in the evaluation pathway once biliary atresia, "red flag" disorders and treatable disorders are excluded. Current therapies focus on promoting bile flow, reducing pruritus, ensuring optimal nutrition, and monitoring for complications, without addressing the underlying cause of cholestasis in most instances. Our improved understanding of bile formation and the enterohepatic circulation of bile acids has led to emerging therapies for cholestasis which require appropriate pediatric clinical trials. Despite these advances, the cause and optimal therapy for biliary atresia remain elusive. The goals of this review are to outline the etiologies, diagnostic pathways and current and emerging management strategies for neonatal cholestasis.
Collapse
Affiliation(s)
- Amy G. Feldman
- Pediatric Liver Center, Digestive Health Institute, Children’s Hospital Colorado, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Ronald J. Sokol
- Pediatric Liver Center, Digestive Health Institute, Children’s Hospital Colorado, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, Colorado, USA,Colorado Clinical and Translational Sciences Institute, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA,Corresponding Author: Ronald J. Sokol, Digestive Health Institute, Children’s Hospital Colorado, Box B290, 13123 E. 16th Ave., Aurora, Colorado, 80045, USA Phone: 720-777-6669, Fax: 720-777-7277,
| |
Collapse
|
|
42
|
Kriegermeier A, Green R. Pediatric Cholestatic Liver Disease: Review of Bile Acid Metabolism and Discussion of Current and Emerging Therapies. Front Med (Lausanne) 2020; 7:149. [PMID: 32432119 PMCID: PMC7214672 DOI: 10.3389/fmed.2020.00149] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Accepted: 04/06/2020] [Indexed: 02/06/2023] Open
Abstract
Cholestatic liver diseases are a significant cause of morbidity and mortality and the leading indication for pediatric liver transplant. These include diseases such as biliary atresia, Alagille syndrome, progressive intrahepatic cholestasis entities, ductal plate abnormalities including Caroli syndrome and congenital hepatic fibrosis, primary sclerosing cholangitis, bile acid synthesis defects, and certain metabolic disease. Medical management of these patients typically includes supportive care for complications of chronic cholestasis including malnutrition, pruritus, and portal hypertension. However, there are limited effective interventions to prevent progressive liver damage in these diseases, leaving clinicians to ultimately rely on liver transplantation in many cases. Agents such as ursodeoxycholic acid, bile acid sequestrants, and rifampicin have been mainstays of treatment for years with the understanding that they may decrease or alter the composition of the bile acid pool, though clinical response to these medications is frequently insufficient and their effects on disease progression remain limited. Recently, animal and human studies have identified potential new therapeutic targets which may disrupt the enterohepatic circulation of bile acids, alter the expression of bile acid transporters or decrease the production of bile acids. In this article, we will review bile formation, bile acid signaling, and the relevance for current and newer therapies for pediatric cholestasis. We will also highlight further areas of potential targets for medical intervention for pediatric cholestatic liver diseases.
Collapse
Affiliation(s)
- Alyssa Kriegermeier
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Feinberg School of Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Chicago, IL, United States
| | - Richard Green
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| |
Collapse
|
|
43
|
Gerussi A, Lucà M, Cristoferi L, Ronca V, Mancuso C, Milani C, D'Amato D, O'Donnell SE, Carbone M, Invernizzi P. New Therapeutic Targets in Autoimmune Cholangiopathies. Front Med (Lausanne) 2020; 7:117. [PMID: 32318580 PMCID: PMC7154090 DOI: 10.3389/fmed.2020.00117] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Accepted: 03/18/2020] [Indexed: 12/12/2022] Open
Abstract
Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are autoimmune cholangiopathies characterized by limited treatment options. A more accurate understanding of the several pathways involved in these diseases has fostered the development of novel and promising targeted drugs. For PBC, the characterization of the role of farnesoid X receptor (FXR) and perixosome-proliferator activated receptor (PPAR) has paved the way to several clinical trials including different molecules with choleretic and antinflammatory action. Conversely, different pathogenetic models have been proposed in PSC such as the "leaky gut" hypothesis, a dysbiotic microbiota or a defect in mechanisms protecting against bile acid toxicity. Along these theories, new treatment approaches have been developed, ranging from drugs interfering with trafficking of lymphocytes from the gut to the liver, fecal microbiota transplantation or new biliary acids with possible immunomodulatory potential. Finally, for both diseases, antifibrotic agents are under investigation. In this review, we will illustrate current understanding of molecular mechanisms in PBC and PSC, focusing on actionable biological pathways for which novel treatments are being developed.
Collapse
Affiliation(s)
- Alessio Gerussi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Martina Lucà
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Laura Cristoferi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Vincenzo Ronca
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
- National Institute of Health Research Liver Biomedical Research Centre Birmingham, Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Clara Mancuso
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Chiara Milani
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Daphne D'Amato
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Sarah Elizabeth O'Donnell
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Marco Carbone
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| |
Collapse
|
|
44
|
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
|
|
45
|
Kennedy L, Meadows V, Kyritsi K, Pham L, Kundu D, Kulkarni R, Cerritos K, Demieville J, Hargrove L, Glaser S, Zhou T, Jaeger V, Alpini G, Francis H. Amelioration of Large Bile Duct Damage by Histamine-2 Receptor Vivo-Morpholino Treatment. THE AMERICAN JOURNAL OF PATHOLOGY 2020; 190:1018-1029. [PMID: 32142732 DOI: 10.1016/j.ajpath.2020.01.013] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 01/22/2020] [Accepted: 01/23/2020] [Indexed: 02/08/2023]
Abstract
Histamine binds to one of the four G-protein-coupled receptors expressed by large cholangiocytes and increases large cholangiocyte proliferation via histamine-2 receptor (H2HR), which is increased in patients with primary sclerosing cholangitis (PSC). Ranitidine decreases liver damage in Mdr2-/- (ATP binding cassette subfamily B member 4 null) mice. We targeted hepatic H2HR in Mdr2-/- mice using vivo-morpholino. Wild-type and Mdr2-/- mice were treated with mismatch or H2HR vivo-morpholino by tail vein injection for 1 week. Liver damage, mast cell (MC) activation, biliary H2HR, and histamine serum levels were studied. MC markers were determined by quantitative real-time PCR for chymase and c-kit. Intrahepatic biliary mass was detected by cytokeratin-19 and F4/80 to evaluate inflammation. Biliary senescence was determined by immunofluorescence and senescence-associated β-galactosidase staining. Hepatic fibrosis was evaluated by staining for desmin, Sirius Red/Fast Green, and vimentin. Immunofluorescence for transforming growth factor-β1, vascular endothelial growth factor-A/C, and cAMP/ERK expression was performed. Transforming growth factor-β1 and vascular endothelial growth factor-A secretion was measured in serum and/or cholangiocyte supernatant. Treatment with H2HR vivo-morpholino in Mdr2-/--mice decreased hepatic damage; H2HR protein expression and MC presence or activation; large intrahepatic bile duct mass, inflammation and senescence; and fibrosis, angiogenesis, and cAMP/phospho-ERK expression. Inhibition of H2HR signaling ameliorates large ductal PSC-induced damage. The H2HR axis may be targeted in treating PSC.
Collapse
Affiliation(s)
- Lindsey Kennedy
- Office of Research, Richard L. Roudebush Veterans Affairs Medical Center, Indianapolis, Indiana; Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Vik Meadows
- Office of Research, Richard L. Roudebush Veterans Affairs Medical Center, Indianapolis, Indiana; Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Konstantina Kyritsi
- Office of Research, Richard L. Roudebush Veterans Affairs Medical Center, Indianapolis, Indiana; Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Linh Pham
- Office of Research, Richard L. Roudebush Veterans Affairs Medical Center, Indianapolis, Indiana; Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Medical Science & Mathematics, Texas A&M University, College Station, Texas
| | - Debjyoti Kundu
- Office of Research, Richard L. Roudebush Veterans Affairs Medical Center, Indianapolis, Indiana; Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Rewa Kulkarni
- Office of Research, Richard L. Roudebush Veterans Affairs Medical Center, Indianapolis, Indiana; Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Karla Cerritos
- Office of Research, Richard L. Roudebush Veterans Affairs Medical Center, Indianapolis, Indiana; Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Jennifer Demieville
- Research Department, Central Texas Veterans Health Care System, Temple, Texas
| | - Laura Hargrove
- Department of Physiology, Texas A&M University, College Station, Texas
| | - Shannon Glaser
- Department of Physiology, Texas A&M University, College Station, Texas
| | - Tianhao Zhou
- Department of Physiology, Texas A&M University, College Station, Texas
| | - Victoria Jaeger
- Department of Physiology, Texas A&M University, College Station, Texas
| | - Gianfranco Alpini
- Office of Research, Richard L. Roudebush Veterans Affairs Medical Center, Indianapolis, Indiana; Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Heather Francis
- Office of Research, Richard L. Roudebush Veterans Affairs Medical Center, Indianapolis, Indiana; Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
| |
Collapse
|
|
46
|
Li T, Xu L, Zheng R, Wang X, Li L, Ji H, Hu Q. Picroside II protects against cholestatic liver injury possibly through activation of farnesoid X receptor. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2020; 68:153153. [PMID: 32018210 DOI: 10.1016/j.phymed.2019.153153] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Revised: 11/13/2019] [Accepted: 12/15/2019] [Indexed: 06/10/2023]
Abstract
BACKGROUD Cholestasis, accompanied by the accumulation of bile acids in body, may ultimately cause liver failure and cirrhosis. There have been limited therapies for cholesteric disorders. Therefore, development of appropriate therapeutic drugs for cholestasis is required. Picroside II is a bioactive component isolated from Picrorhiza scrophulariiflora Pennell, its mechanistic contributions to the anti-cholestasis effect have not been fully elucidated, especially the role of picroside II on bile acid homeostasis via nuclear receptors remains unclear. PURPOSE This study was designed to investigate the hepatoprotective effect of picroside II against alpha-naphthylisothiocyanate (ANIT)-induced cholestatic liver injury and elucidate the mechanisms in vivo and in vitro. METHODS The ANIT-induced cholestatic mouse model was used with or without picroside II treatment. Serum and bile biochemical indicators, as well as liver histopathological changes were examined. siRNA, Dual-luciferase reporter, quantitative real-time PCR and Western blot assay were used to demonstrate the farnesoid X receptor (FXR) pathway in the anti-cholestasis effects of picroside II in vivo and in vitro. RESULTS Picroside II exerted hepatoprotective effect against ANIT-induced cholestasis by impaired hepatic function and tissue damage. Picroside II increased bile acid efflux transporter bile salt export pump (Bsep), uptake transporter sodium taurocholate cotransporting polypeptide (Ntcp), and bile acid metabolizing enzymes sulfate transferase 2a1 (Sult2a1) and UDP-glucuronosyltransferase 1a1 (Ugt1a1), whereas decreased the bile acid synthesis enzymes cholesterol 7α-hydroxylase (Cyp7a1) and oxysterol 12α-hydroxylase (Cyp8b1). In addition, expression of FXR and the target gene Bsep was increased, whereas aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR), peroxisome proliferator-activated receptor alpha (PPARα) and their corresponding target genes were not significantly influenced by picroside II under cholestatic conditions. Furthermore, regulation of transporters and enzymes involved in bile acid homeostasis by picroside II were abrogated by FXR silencing in mouse primary cultured hepatocytes. Dual-luciferase reporter assay performed in HepG2 cells demonstrated FXR activation by picroside II. CONCLUSION Our findings demonstrate that picroside II exerts protective effect on ANIT-induced cholestasis possibly through FXR activation that regulates the transporters and enzymes involved in bile acid homeostasis. Picroside II might be an effective approach for the prevention and treatment of cholestatic liver diseases.
Collapse
Affiliation(s)
- Tingting Li
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Lijie Xu
- School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China; Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai 200080, China
| | - Rongyao Zheng
- School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Xinjie Wang
- School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Liwen Li
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Hui Ji
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
| | - Qinghua Hu
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
| |
Collapse
|
|
47
|
Abstract
Though ursodeoxycholic acid (UDCA) remains the baseline treatment for most cholestatic liver diseases, UDCA treatment leaves approximately one-third of patients with primary biliary cholangitis (PBC) and all patients with primary sclerosing cholangitis (PSC) at risk for disease progression. New anticholestatic agents, including nuclear receptor agonists, choleretics, and bile acid synthesis suppressors, will likely increase response rates to therapy in PBC and PSC. Strategies that target early immune-mediated injury have so far been disappointing, hampered by the lack of biomarkers to detect early disease states, which then could profit from immunomodulatory therapy. Future concepts need to personalize treatments according to disease stage, progression, and phase, and to combine multiple drugs to target different pathogenic pathways.
Collapse
Affiliation(s)
- Martin Wagner
- Division of Gastroenterology and Hepatology, Department of Medicine, Medical University of Graz, 8036 Graz, Austria
| | - Peter Fickert
- Division of Gastroenterology and Hepatology, Department of Medicine, Medical University of Graz, 8036 Graz, Austria
| |
Collapse
|
|
48
|
Gerussi A, D'Amato D, Cristoferi L, O'Donnell SE, Carbone M, Invernizzi P. Multiple therapeutic targets in rare cholestatic liver diseases: Time to redefine treatment strategies. Ann Hepatol 2020; 19:5-16. [PMID: 31771820 DOI: 10.1016/j.aohep.2019.09.009] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 09/27/2019] [Accepted: 09/27/2019] [Indexed: 02/04/2023]
Abstract
Primary biliary cholangitis and primary sclerosing cholangitis are rare diseases affecting the bile ducts and the liver. The limited knowledge of their pathogenesis leads to limited therapeutic options. Nevertheless, the landscape of novel therapies for these cholangiopathies is now rapidly changing, providing new treatment opportunities for patients and clinicians involved in their care. The aim of this review is to summarize the evidence of novel molecules under investigation for primary biliary cholangitis and primary sclerosing cholangitis and to discuss how they can potentially change current treatment paradigms.
Collapse
Affiliation(s)
- Alessio Gerussi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Daphne D'Amato
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Laura Cristoferi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Sarah Elizabeth O'Donnell
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Marco Carbone
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy.
| |
Collapse
|
|
49
|
Emerging therapies in primary sclerosing cholangitis: pathophysiological basis and clinical opportunities. J Gastroenterol 2020; 55:588-614. [PMID: 32222826 PMCID: PMC7242240 DOI: 10.1007/s00535-020-01681-z] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2020] [Accepted: 03/05/2020] [Indexed: 02/04/2023]
Abstract
Primary sclerosing cholangitis (PSC) is a progressive liver disease, histologically characterized by inflammation and fibrosis of the bile ducts, and clinically leading to multi-focal biliary strictures and with time cirrhosis and liver failure. Patients bear a significant risk of cholangiocarcinoma and colorectal cancer, and frequently have concomitant inflammatory bowel disease and autoimmune disease manifestations. To date, no medical therapy has proven significant impact on clinical outcomes and most patients ultimately need liver transplantation. Several treatment strategies have failed in the past and whilst prescription of ursodeoxycholic acid (UDCA) prevails, controversy regarding benefits remains. Lack of statistical power, slow and variable disease progression, lack of surrogate biomarkers for disease severity and other challenges in trial design serve as critical obstacles in the development of effective therapy. Advances in our understanding of PSC pathogenesis and biliary physiology over recent years has however led to a surge of clinical trials targeting various mechanistic compartments and currently raising hopes for imminent changes in patient management. Here, in light of pathophysiology, we outline and critically evaluate emerging treatment strategies in PSC, as tested in recent or ongoing phase II and III trials, stratified per a triad of targets of nuclear and membrane receptors regulating bile acid metabolism, immune modulators, and effects on the gut microbiome. Furthermore, we revisit the UDCA trials of the past and critically discuss relevant aspects of clinical trial design, including how the choice of endpoints, alkaline phosphatase in particular, may affect the future path to novel, effective PSC therapeutics.
Collapse
|
|
50
|
Zhai Q, Wang J, Cen S, Zhao J, Zhang H, Tian F, Chen W. Modulation of the gut microbiota by a galactooligosaccharide protects against heavy metal lead accumulation in mice. Food Funct 2019; 10:3768-3781. [PMID: 31180403 DOI: 10.1039/c9fo00587k] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The heavy metal lead (Pb) is a toxic contaminant that induces a range of adverse effects in humans. The present study demonstrated for the first time that dietary supplementation with a galactooligosaccharide (GOS) promotes fecal Pb excretion and reduces Pb accumulation in the blood and tissues of mice. The effects against Pb exposure were also observed in mice that received the fecal microbiota from donors treated with GOS, but were diminished in gut microbiota-depleted mice that received antibiotic pre-treatment, indicating that the protection by GOS administration was dependent on the modulation of the gut microbiota. We also provide evidence that the protective mechanism of GOS supplementation was related to the enhanced abundance of intestinal bacteria with good Pb-binding ability, recovery of the gut barrier function, modulation of bile acid metabolism, and improved essential metal utilization. These results indicate that GOS can be considered a potentially protective prebiotic against Pb toxicity.
Collapse
Affiliation(s)
- Qixiao Zhai
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, China.
| | | | | | | | | | | | | |
Collapse
|