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Imran M, Elsnhory AB, Ibrahim AA, Elnaggar M, Tariq MS, Mehmood AM, Ali S, Khalil S, Khan SH, Ali M, Abuelazm M. Efficacy and Safety of Ileal Bile Acid Transport Inhibitors in Inherited Cholestatic Liver Disorders: A Meta-analysis of Randomized Controlled Trials. J Clin Exp Hepatol 2025; 15:102462. [PMID: 39802553 PMCID: PMC11720443 DOI: 10.1016/j.jceh.2024.102462] [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: 07/29/2024] [Accepted: 11/15/2024] [Indexed: 01/16/2025] Open
Abstract
Background Inherited cholestatic liver disorders such as progressive familial intrahepatic cholestasis (PFIC) and Alagille syndrome result in significant pruritus and increased serum bile acids, necessitating liver transplantation. This study aims to evaluate the efficacy and safety of Ileal bile acid transport inhibitors (IBATIs) in children with PFIC and Alagille syndrome. Methods We conducted a comprehensive search across the databases to identify relevant randomized controlled trials (RCTs), and Covidence was used to screen eligible articles. All outcomes data were synthesized using risk ratios (RRs) or mean differences (MDs) with 95% confidence intervals (CIs) in RevMan 5.4. PROSPERO: CRD42024564270. Results Four multicenter RCTs involving 215 patients were included. IBATIs were associated with a significant reduction in Itch Observer Reported Outcome (Itch (ObsRo)) score (MD: -0.90, 95% CI [-1.17, -0.63], P < 0.01), serum bile acids (MD: -119.06, 95% CI [-152.37, -85.74], P < 0.01), total bilirubin (MD: -0.73, 95% CI [-1.32, -0.15], P = 0.01), and increased proportion of patients achieving ≥1 score reduction in Itch (ObsRo) score (RR: 2.54, 95% CI [3.83, 1.69], P < 0.01) and bile acid responders (RR: 8.76, 95% CI [2.46, 31.23], P < 0.01) compared with placebo. No differences were observed in any treatment-emergent adverse events (TEAs) (RR: 1.02, 95% CI [1.12, 0.93], P = 0.71), TEAs leading to drug discontinuation (1.03, 95% CI [5.56, 0.19], any serious TEAs, or liver-related TEAs. Conclusion IBATIs showed significant improvement in various cholestatic parameters with tolerable safety profile; however, future research on optimal dosage and long-term outcomes is needed.
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Affiliation(s)
- Muhammad Imran
- University College of Medicine and Dentistry, The University of Lahore, Lahore, Pakistan
| | | | | | | | | | | | - Shujaat Ali
- University College of Medicine and Dentistry, The University of Lahore, Lahore, Pakistan
| | - Saba Khalil
- Faculty of Medicine, Fatima Jinnah Medical University, Lahore, Pakistan
| | - Sheharyar H. Khan
- Department of Medicine, University Hospitals of Derby and Burton NHS Foundation Trust, UK
| | - Mansab Ali
- University College of Medicine and Dentistry, The University of Lahore, Lahore, Pakistan
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Liu Y, Zhu J, Jin Y, Sun Z, Wu X, Zhou H, Yang Y. Disrupting bile acid metabolism by suppressing Fxr causes hepatocellular carcinoma induced by YAP activation. Nat Commun 2025; 16:3583. [PMID: 40234449 PMCID: PMC12000370 DOI: 10.1038/s41467-025-58809-z] [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: 08/09/2024] [Accepted: 04/03/2025] [Indexed: 04/17/2025] Open
Abstract
Disruption of bile acid (BA) metabolism causes various liver diseases including hepatocellular carcinoma (HCC). However, the underlying molecular mechanism remains elusive. Here, we report that BA metabolism is directly controlled by a repressor function of YAP, which induces cholestasis by altering BA levels and composition via inhibiting the transcription activity of Fxr, a key physiological BA sensor. Elevated BA levels further activate hepatic YAP, resulting in a feedforward cycle leading to HCC. Mechanistically, Teads are found to bind Fxr in a DNA-binding-independent manner and recruit YAP to epigenetically suppress Fxr. Promoting BA excretion, or alleviating YAP repressor function by pharmacologically activating Fxr and inhibiting HDAC1, or overexpressing an Fxr target gene Bsep to promote BA exportation, alleviate cholestasis and HCC caused by YAP activation. Our results identify YAP's transcriptional repressor role in BA metabolism as a key driver of HCC and suggest its potential as a therapeutic target.
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MESH Headings
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/pathology
- Liver Neoplasms/metabolism
- Liver Neoplasms/genetics
- Liver Neoplasms/pathology
- Humans
- Bile Acids and Salts/metabolism
- YAP-Signaling Proteins
- Animals
- Receptors, Cytoplasmic and Nuclear/metabolism
- Receptors, Cytoplasmic and Nuclear/genetics
- Transcription Factors/metabolism
- Transcription Factors/genetics
- Mice
- Adaptor Proteins, Signal Transducing/metabolism
- Adaptor Proteins, Signal Transducing/genetics
- Male
- ATP Binding Cassette Transporter, Subfamily B, Member 11/metabolism
- ATP Binding Cassette Transporter, Subfamily B, Member 11/genetics
- Cell Line, Tumor
- Cell Cycle Proteins/metabolism
- Cholestasis/metabolism
- Cholestasis/genetics
- Gene Expression Regulation, Neoplastic
- Liver/metabolism
- Liver/pathology
- Hep G2 Cells
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Affiliation(s)
- Yuchen Liu
- Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA
| | - Juanjuan Zhu
- Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA
| | - Yu Jin
- Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA
| | - Zhonghe Sun
- Cancer Research Technology Program, Frederick National Laboratory for Cancer, Frederick, MD, USA
| | - Xiaolin Wu
- Cancer Research Technology Program, Frederick National Laboratory for Cancer, Frederick, MD, USA
| | - Huiping Zhou
- Department of Microbiology & Immunology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Yingzi Yang
- Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA.
- Harvard Stem Cell Institute, Cambridge, MA, USA.
- Program in Gastrointestinal Malignancies, Dana-Farber/Harvard Cancer Center, Boston, MA, USA.
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De Vos K, Mols R, Chatterjee S, Huang MC, Augustijns P, Wolters JC, Annaert P. In Vitro-In Silico Models to Elucidate Mechanisms of Bile Acid Disposition and Cellular Aerobics in Human Hepatocytes. AAPS J 2025; 27:51. [PMID: 40016501 DOI: 10.1208/s12248-024-01010-9] [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: 09/16/2024] [Accepted: 12/08/2024] [Indexed: 03/01/2025] Open
Abstract
Understanding the kinetics of hepatic processes, such as bile acid (BA) handling and cellular aerobic metabolism, is crucial for advancing our knowledge of liver toxicity, particularly drug-induced cholestasis (DiCho). This article aimed to construct interpretable models with parameter estimations serving as reference values when investigating these cell metrics. Longitudinal datasets on BA disposition and oxygen consumption rates were collected using sandwich-cultured human hepatocytes. Chenodeoxycholic acid (CDCA), lithocholic acid (LCA), as well as their amidated and sulfate-conjugated metabolites were quantified with liquid chromatography-mass spectrometry. The bile salt export pump (BSEP) abundance was monitored with targeted proteomics and modelled for activity assessment. Oxygen consumption was measured using Seahorse XFp analyser. Ordinary differential equation-based models were solved in R. The basolateral uptake and efflux clearance of glycine-conjugated CDCA (GCDCA) were estimated at 1.22 µL/min/106 cells (RSE 14%) and 0.11 µL/min/106 cells (RSE 10%), respectively. The GCDCA clearance from canaliculi back to the medium was 2.22 nL/min/106 cells (RSE 17%), and the dissociation constant between (G)CDCA and FXR for regulating BSEP abundance was 25.73 nM (RSE 11%). Sulfation clearance for LCA was 0.19 µL/min/106 cells (RSE 11%). Model performance was further demonstrated by a maximum two-fold deviation of the 95% confidence boundaries from parameter estimates. These in vitro-in silico models provide a quantitative framework for exploring xenobiotic impacts on BA disposition, BSEP activity, and cellular aerobic metabolism in hepatocytes. Model simulations were consistent with reported in vivo data in progressive familial intrahepatic cholestasis type II patients.
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Affiliation(s)
- Kristof De Vos
- Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, Herestraat 49, KU Leuven, 3000, Leuven, Belgium
| | - Raf Mols
- Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, Herestraat 49, KU Leuven, 3000, Leuven, Belgium
| | - Sagnik Chatterjee
- DMPK Department, AstraZeneca, Västra Götaland County, Gothenburg, Sweden
| | - Miao-Chan Huang
- Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, Herestraat 49, KU Leuven, 3000, Leuven, Belgium
| | - Patrick Augustijns
- Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, Herestraat 49, KU Leuven, 3000, Leuven, Belgium
| | - Justina Clarinda Wolters
- Section Systems Medicine of Metabolism and Signaling, Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, 9713 AV, The Netherlands
| | - Pieter Annaert
- Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, Herestraat 49, KU Leuven, 3000, Leuven, Belgium.
- BioNotus GCV, 2845, Niel, Belgium.
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Angendohr C, Missing L, Ehlting C, Wolf SD, Lang KS, Vucur M, Luedde T, Bode JG. Interleukin 1 β suppresses bile acid-induced BSEP expression via a CXCR2-dependent feedback mechanism. PLoS One 2024; 19:e0315243. [PMID: 39680527 DOI: 10.1371/journal.pone.0315243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Accepted: 11/22/2024] [Indexed: 12/18/2024] Open
Abstract
Inflammation-induced cholestasis is a common problem in septic patients and results from cytokine-mediated inhibition of bile acid export including impaired expression of the bile salt export pump (BSEP) with a consecutive increase in intracellular bile acids mediating cell damage. The present study focuses on the mechanisms by which interleukin 1 β (IL-1β), as a critical mediator of sepsis-induced cholestasis, controls the expression of BSEP in hepatocytes. Notably, the treatment of hepatocytes with IL-1β leads to the upregulation of a broad chemokine pattern. Thereby, the IL-1β -induced expression of in particular the CXCR2 ligands CXCL1 and 2 is further enhanced by bile acids, whereas the FXR-mediated upregulation of BSEP induced by bile acids is inhibited by IL-1β. In this context, it is interesting to note that inhibitor studies indicate that IL-1β mediates its inhibitory effects on bile acid-induced expression of BSEP indirectly via CXCR2 ligands. Consistently, inhibition of CXCR2 with the inhibitor SB225002 significantly attenuated of the inhibitory effect of IL-1β on BSEP expression. These data suggest that part of the cholestasis-inducing effect of IL-1β is mediated via a CXCR2-dependent feedback mechanism.
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Affiliation(s)
- Carolin Angendohr
- Faculty of Medicine & Düsseldorf University Hospital, Department of Gastroenterology, Hepatology and Infectious Disease, Heinrich-Heine-University, Düsseldorf, Germany
| | - Leah Missing
- Faculty of Medicine & Düsseldorf University Hospital, Department of Gastroenterology, Hepatology and Infectious Disease, Heinrich-Heine-University, Düsseldorf, Germany
| | - Christian Ehlting
- Faculty of Medicine & Düsseldorf University Hospital, Department of Gastroenterology, Hepatology and Infectious Disease, Heinrich-Heine-University, Düsseldorf, Germany
| | - Stephanie D Wolf
- Faculty of Medicine & Düsseldorf University Hospital, Department of Gastroenterology, Hepatology and Infectious Disease, Heinrich-Heine-University, Düsseldorf, Germany
| | - Karl S Lang
- Department of Immunology, University of Essen, Essen, Germany
| | - Mihael Vucur
- Faculty of Medicine & Düsseldorf University Hospital, Department of Gastroenterology, Hepatology and Infectious Disease, Heinrich-Heine-University, Düsseldorf, Germany
| | - Tom Luedde
- Faculty of Medicine & Düsseldorf University Hospital, Department of Gastroenterology, Hepatology and Infectious Disease, Heinrich-Heine-University, Düsseldorf, Germany
| | - Johannes G Bode
- Faculty of Medicine & Düsseldorf University Hospital, Department of Gastroenterology, Hepatology and Infectious Disease, Heinrich-Heine-University, Düsseldorf, Germany
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Lu S, Jiang S, Feng J, Chen W, Huang D, Sun L. Two new flavonoid glucosides from Penthorum chinense Pursh. Nat Prod Res 2024:1-7. [PMID: 39520725 DOI: 10.1080/14786419.2024.2426211] [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: 03/07/2024] [Revised: 10/08/2024] [Accepted: 10/30/2024] [Indexed: 11/16/2024]
Abstract
Two new flavonoids, Alpinetin-7-O-[3''-O-galloyl-4'',6''-hexahydroxy-diphenoyl]-β-D-glucose (1), Pinocembrin-7-O-[4''-O-galloyl]-β-D-glucose (2), and three known compound (3-5) were isolated from Penthorum chinense Pursh (Saxifragaceae). The structures of all compounds were deduced from their comprehensive spectroscopic analysis including IR, HR-ESI-MS,1H NMR,13C NMR, DEPT, COSY, HMBC and HMQC. Molecular docking model was used to test the anti-cholestatic liver activities of the isolated compounds, and compounds 1 and 2 showed higher docking scores (-9.90 and -11.27 kcal/mol, respectively) binding with FXR than 3, 4 and 5 (-8.00, -9.77, -9.10 kcal/mol, respectively), suggesting 1 and 2 exhibited potential anti-cholestatic activities. The present results show that P. chinense is a potential source of 2 new lead compounds that can be utilised to produce therapeutic drugs for liver diseases upon further studies.
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Affiliation(s)
- Shengyao Lu
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Songfan Jiang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jingxian Feng
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wansheng Chen
- The MOE Key Laboratory for Standardization of Chinese Medicines, the SHTCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, The MOE Innovation Centre for Basic Medicine Research on Qi-Blood TCM Theories, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Doudou Huang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lianna Sun
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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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.
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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
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Riaz H, Zheng B, Zheng Y, Liu Z, Gu HM, Imran M, Yaqoob T, Bhinder MA, Zhang DW, Zahoor MY. The spectrum of novel ABCB11 gene variations in children with progressive familial intrahepatic cholestasis type 2 in Pakistani cohorts. Sci Rep 2024; 14:18876. [PMID: 39143102 PMCID: PMC11324741 DOI: 10.1038/s41598-024-59945-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Accepted: 04/17/2024] [Indexed: 08/16/2024] Open
Abstract
Progressive familial intrahepatic cholestasis (PFIC) is a rare childhood manifested disease associated with impaired bile secretion with severe pruritus yellow stool, and sometimes hepatosplenomegaly. PFIC is caused by mutations in ATP8B1, ABCB11, ABCB4, TJP2, NR1H4, SLC51A, USP53, KIF12, ZFYVE19, and MYO5B genes depending on its type. ABCB11 mutations lead to PFIC2 that encodes the bile salt export pump (BSEP). Different mutations of ABCB11 have been reported in different population groups but no data available in Pakistani population being a consanguineous one. We sequenced coding exons of the ABCB11 gene along with its flanking regions in 66 unrelated Pakistani children along with parents with PFIC2 phenotype. We identified 20 variations of ABCB11: 12 in homozygous form, one compound heterozygous, and seven heterozygous. These variants include 11 missenses, two frameshifts, two nonsense mutations, and five splicing variants. Seven variants are novel candidate variants and are not detected in any of the 120 chromosomes from normal ethnically matched individuals. Insilico analysis revealed that four homozygous missense variations have high pathogenic scores. Minigene analysis of splicing variants showed exon skipping and the addition of exon. This data is a useful addition to the disease variants genomic database and would be used in the future to build a diagnostic algorithm.
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Affiliation(s)
- Hafsa Riaz
- Department of Pediatrics, University of Alberta, Edmonton, Canada
- Institute of Biochemistry and Biotechnology, University of Veterinary and Animal Sciences, Lahore, Pakistan
| | - Bixia Zheng
- Department of Gastroenterology, Children's Hospital of Nanjing Medical University, Nanjing, People's Republic of China
| | - Yucan Zheng
- Department of Gastroenterology, Children's Hospital of Nanjing Medical University, Nanjing, People's Republic of China
| | - Zhifeng Liu
- Department of Gastroenterology, Children's Hospital of Nanjing Medical University, Nanjing, People's Republic of China
| | - Hong-Mei Gu
- Department of Pediatrics, University of Alberta, Edmonton, Canada
| | - Muhammad Imran
- Institute of Biochemistry and Biotechnology, University of Veterinary and Animal Sciences, Lahore, Pakistan
| | - Tahir Yaqoob
- Institute of Microbiology, University of Veterinary and Animal Sciences, Lahore, Pakistan
| | - Munir Ahmad Bhinder
- Department of Human Genetics and Molecular Biology, University of Health Sciences, Lahore, Pakistan
| | - Da-Wei Zhang
- Department of Pediatrics, University of Alberta, Edmonton, Canada.
| | - Muhammad Yasir Zahoor
- Institute of Biochemistry and Biotechnology, University of Veterinary and Animal Sciences, Lahore, Pakistan.
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Wakabayashi N, Yagishita Y, Joshi T, Kensler TW. Dual Deletion of Keap1 and Rbpjκ Genes in Liver Leads to Hepatomegaly and Hypercholesterolemia. Int J Mol Sci 2024; 25:4712. [PMID: 38731931 PMCID: PMC11083431 DOI: 10.3390/ijms25094712] [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: 04/11/2024] [Revised: 04/21/2024] [Accepted: 04/23/2024] [Indexed: 05/13/2024] Open
Abstract
The hepatic deletion of Rbpjκ (RbpjF/F::AlbCre) in the mouse leads to exhibition of the Alagille syndrome phenotype during early postnatal liver development with hyperlipidemia and cholestasis due to attenuated disruption of NOTCH signaling. Given the roles of NRF2 signaling in the regulation of lipid metabolism and bile ductal formation, it was anticipated that these symptoms could be alleviated by enhancing NRF2 signaling in the RbpjF/F::AlbCre mouse by hepatic deletion of Keap1 in compound Keap1F/F::RbpjF/F::AlbCre mice. Unexpectedly, these mice developed higher hepatic and plasma cholesterol levels with more severe cholestatic liver damage during the pre-weaning period than in the RbpjF/F::AlbCre mice. In addition, hypercholesterolemia and hepatic damage were sustained throughout the growth period unlike in the RbpjF/F::AlbCre mouse. These enhanced abnormalities in lipid metabolism appear to be due to NRF2-dependent changes in gene expression related to cholesterol synthetic and subsequent bile acid production pathways. Notably, the hepatic expression of Cyp1A7 and Abcb11 genes involved in bile acid homeostasis was significantly reduced in Keap1F/F::RbpjF/F::AlbCre compared to RbpjF/F::AlbCre mice. The accumulation of liver cholesterol and the weakened capacity for bile excretion during the 3 pre-weaning weeks in the Keap1F/F::RbpjF/F::AlbCre mice may aggravate hepatocellular damage level caused by both excessive cholesterol and residual bile acid toxicity in hepatocytes. These results indicate that a tuned balance of NOTCH and NRF2 signaling is of biological importance for early liver development after birth.
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Affiliation(s)
- Nobunao Wakabayashi
- Translational Research Program, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; (N.W.); (T.J.)
| | - Yoko Yagishita
- Translational Research Program, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; (N.W.); (T.J.)
- Division of Endocrinology, Columbia University, New York, NY 10032, USA
| | - Tanvi Joshi
- Translational Research Program, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; (N.W.); (T.J.)
| | - Thomas W. Kensler
- Translational Research Program, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; (N.W.); (T.J.)
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Wakasa K, Tamura R, Osaka S, Takei H, Asai A, Nittono H, Kusuhara H, Hayashi H. Rapid in vivo evaluation system for cholestasis-related genes in mice with humanized bile acid profiles. Hepatol Commun 2024; 8:e0382. [PMID: 38517206 PMCID: PMC10962888 DOI: 10.1097/hc9.0000000000000382] [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] [Received: 07/24/2023] [Accepted: 12/05/2023] [Indexed: 03/23/2024] Open
Abstract
BACKGROUND Pediatric cholestatic liver diseases (Ped-CLD) comprise many ultrarare disorders with a genetic basis. Pharmacologic therapy for severe cases of Ped-CLD has not been established. Species differences in bile acid (BA) metabolism between humans and rodents contribute to the lack of phenocopy of patients with Ped-CLD in rodents and hinder the development of therapeutic strategies. We aimed to establish an efficient in vivo system to understand BA-related pathogenesis, such as Ped-CLD. METHODS We generated mice that express spCas9 specifically in the liver (L-Cas9Tg/Tg [liver-specific Cas9Tg/Tg] mice) and designed recombinant adeno-associated virus serotype 8 encoding small-guide RNA (AAV8 sgRNA) targeting Abcc2, Abcb11, and Cyp2c70. In humans, ABCC2 and ABCB11 deficiencies cause constitutional hyperbilirubinemia and most severe Ped-CLD, respectively. Cyp2c70 encodes an enzyme responsible for the rodent-specific BA profile. Six-week-old L-Cas9Tg/Tg mice were injected with this AAV8 sgRNA and subjected to biochemical and histological analysis. RESULTS Fourteen days after the injection with AAV8 sgRNA targeting Abcc2, L-Cas9Tg/Tg mice exhibited jaundice and phenocopied patients with ABCC2 deficiency. L-Cas9Tg/Tg mice injected with AAV8 sgRNA targeting Abcb11 showed hepatomegaly and cholestasis without histological evidence of liver injury. Compared to Abcb11 alone, simultaneous injection of AAV8 sgRNA for Abcb11 and Cyp2c70 humanized the BA profile and caused higher transaminase levels and parenchymal necrosis, resembling phenotypes with ABCB11 deficiency. CONCLUSIONS This study provides proof of concept for efficient in vivo assessment of cholestasis-related genes in humanized bile acid profiles. Our platform offers a more time- and cost-effective alternative to conventional genetically engineered mice, increasing our understanding of BA-related pathogenesis such as Ped-CLD and expanding the potential for translational research.
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Affiliation(s)
- Kihiro Wakasa
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo, Japan
| | - Ryutaro Tamura
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo, Japan
| | - Shuhei Osaka
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo, Japan
| | - Hajime Takei
- Junshin Clinic Bile Acid Institute, Tokyo, Japan
| | - Akihiro Asai
- Department of Gastroenterology, and Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | | | - Hiroyuki Kusuhara
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo, Japan
| | - Hisamitsu Hayashi
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo, Japan
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Kondou H, Nakano S, Mizuno T, Bessho K, Hasegawa Y, Nakazawa A, Tanikawa K, Azuma Y, Okamoto T, Inui A, Imagawa K, Kasahara M, Zen Y, Suzuki M, Hayashi H. Clinical symptoms, biochemistry, and liver histology during the native liver period of progressive familial intrahepatic cholestasis type 2. Orphanet J Rare Dis 2024; 19:57. [PMID: 38341604 PMCID: PMC10858576 DOI: 10.1186/s13023-024-03080-6] [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: 05/22/2023] [Accepted: 02/05/2024] [Indexed: 02/12/2024] Open
Abstract
BACKGROUND Progressive familial intrahepatic cholestasis type 2 (PFIC2) is an ultra-rare disease caused by mutations in the ABCB11 gene. This study aimed to understand the course of PFIC2 during the native liver period. METHODS From November 2014 to October 2015, a survey to identify PFIC2 patients was conducted in 207 hospitals registered with the Japanese Society of Pediatric Gastroenterology, Hepatology, and Nutrition. Investigators retrospectively collected clinical data at each facility in November 2018 using pre-specified forms. RESULTS Based on the biallelic pathogenic variants in ABCB11 and/or no hepatic immunohistochemical detection of BSEP, 14 Japanese PFIC2 patients were enrolled at seven facilities. The median follow-up was 63.2 [47.7-123.3] months. The median age of disease onset was 2.5 [1-4] months. Twelve patients underwent living donor liver transplantation (LDLT), with a median age at LDLT of 9 [4-57] months. Two other patients received sodium 4-phenylbutyrate (NaPB) therapy and survived over 60 months with the native liver. No patients received biliary diversion. The cases that resulted in LDLT had gradually deteriorated growth retardation, biochemical tests, and liver histology since the initial visit. In the other two patients, jaundice, growth retardation, and most of the biochemical tests improved after NaPB therapy was started, but pruritus and liver fibrosis did not. CONCLUSIONS Japanese PFIC2 patients had gradually worsening clinical findings since the initial visit, resulting in LDLT during infancy. NaPB therapy improved jaundice and growth retardation but was insufficient to treat pruritus and liver fibrosis.
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Affiliation(s)
- Hiroki Kondou
- Department of Pediatrics, Kindai University Nara Hospital, Nara, Japan
| | - Satoshi Nakano
- Department of Pediatrics, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Tadahaya Mizuno
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo, Japan
| | - Kazuhiko Bessho
- Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Yasuhiro Hasegawa
- Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Atsuko Nakazawa
- Department of Clinical Research, Saitama Children's Medical Center, Saitama, Japan
| | - Ken Tanikawa
- Department of Diagnostic Pathology, Kurume University Hospital, Fukuoka, Japan
| | - Yoshihiro Azuma
- Department of Pediatrics, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
| | - Tatsuya Okamoto
- Department of Pediatric Surgery, Kyoto University Hospital, Kyoto, Japan
| | - Ayano Inui
- Department of Pediatric Hepatology and Gastroenterology, Saiseikai Yokohama City Eastern Hospital, Kanagawa, Japan
| | - Kazuo Imagawa
- Department of Pediatrics, University of Tsukuba Hospital, Ibaraki, Japan
| | - Mureo Kasahara
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| | - Yoh Zen
- Institute of Liver Studies, King's College Hospital and King's College London, London, UK
| | - Mitsuyoshi Suzuki
- Department of Pediatrics, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Hisamitsu Hayashi
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo, Japan.
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11
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Cheng K, Rosenthal P. Diagnosis and management of Alagille and progressive familial intrahepatic cholestasis. Hepatol Commun 2023; 7:e0314. [PMID: 38055640 PMCID: PMC10984671 DOI: 10.1097/hc9.0000000000000314] [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: 05/30/2023] [Accepted: 09/12/2023] [Indexed: 12/08/2023] Open
Abstract
Alagille syndrome and progressive familial intrahepatic cholestasis are conditions that can affect multiple organs. Advancements in molecular testing have aided in the diagnosis of both. The impairment of normal bile flow and secretion leads to the various hepatic manifestations of these diseases. Medical management of Alagille syndrome and progressive familial intrahepatic cholestasis remains mostly targeted on supportive care focusing on quality of life, cholestasis, and fat-soluble vitamin deficiency. The most difficult therapeutic issue is typically related to pruritus, which can be managed by various medications such as ursodeoxycholic acid, rifampin, cholestyramine, and antihistamines. Surgical operations were previously used to disrupt enterohepatic recirculation, but recent medical advancements in the use of ileal bile acid transport inhibitors have shown great efficacy for the treatment of pruritus in both Alagille syndrome and progressive familial intrahepatic cholestasis.
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Affiliation(s)
- Katherine Cheng
- Department of Pediatrics Gastroenterology, Hepatology and Nutrition, University of California San Francisco, San Francisco, California, USA
| | - Philip Rosenthal
- Department of Pediatrics Gastroenterology, Hepatology and Nutrition, University of California San Francisco, San Francisco, California, USA
- Department of Surgery, University of California, San Francisco, San Francisco, California, USA
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12
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Tamura R, Sabu Y, Mizuno T, Mizuno S, Nakano S, Suzuki M, Abukawa D, Kaji S, Azuma Y, Inui A, Okamoto T, Shimizu S, Fukuda A, Sakamoto S, Kasahara M, Takahashi S, Kusuhara H, Zen Y, Ando T, Hayashi H. Intestinal Atp8b1 dysfunction causes hepatic choline deficiency and steatohepatitis. Nat Commun 2023; 14:6763. [PMID: 37990006 PMCID: PMC10663612 DOI: 10.1038/s41467-023-42424-x] [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: 06/09/2023] [Accepted: 10/11/2023] [Indexed: 11/23/2023] Open
Abstract
Choline is an essential nutrient, and its deficiency causes steatohepatitis. Dietary phosphatidylcholine (PC) is digested into lysoPC (LPC), glycerophosphocholine, and choline in the intestinal lumen and is the primary source of systemic choline. However, the major PC metabolites absorbed in the intestinal tract remain unidentified. ATP8B1 is a P4-ATPase phospholipid flippase expressed in the apical membrane of the epithelium. Here, we use intestinal epithelial cell (IEC)-specific Atp8b1-knockout (Atp8b1IEC-KO) mice. These mice progress to steatohepatitis by 4 weeks. Metabolomic analysis and cell-based assays show that loss of Atp8b1 in IEC causes LPC malabsorption and thereby hepatic choline deficiency. Feeding choline-supplemented diets to lactating mice achieves complete recovery from steatohepatitis in Atp8b1IEC-KO mice. Analysis of samples from pediatric patients with ATP8B1 deficiency suggests its translational potential. This study indicates that Atp8b1 regulates hepatic choline levels through intestinal LPC absorption, encouraging the evaluation of choline supplementation therapy for steatohepatitis caused by ATP8B1 dysfunction.
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Affiliation(s)
- Ryutaro Tamura
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo, Japan
| | - Yusuke Sabu
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo, Japan
| | - Tadahaya Mizuno
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo, Japan
| | - Seiya Mizuno
- Laboratory Animal Resource Center and Trans-Border Medical Research Center, University of Tsukuba, Ibaraki, Japan
| | - Satoshi Nakano
- Department of Pediatrics, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Mitsuyoshi Suzuki
- Department of Pediatrics, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Daiki Abukawa
- Department of Gastroenterology and Hepatology, Miyagi Children's Hospital, Miyagi, Japan
| | - Shunsaku Kaji
- Department of Pediatrics, Tsuyama-Chuo Hospital, Okayama, Japan
| | - Yoshihiro Azuma
- Department of Pediatrics, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
| | - Ayano Inui
- Department of Pediatric Hepatology and Gastroenterology, Saiseikai Yokohama City Eastern Hospital, Kanagawa, Japan
| | - Tatsuya Okamoto
- Department of Pediatric Surgery, Kyoto University Hospital, Kyoto, Japan
| | - Seiichi Shimizu
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| | - Akinari Fukuda
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| | - Seisuke Sakamoto
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| | - Mureo Kasahara
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| | - Satoru Takahashi
- Laboratory Animal Resource Center and Trans-Border Medical Research Center, University of Tsukuba, Ibaraki, Japan
| | - Hiroyuki Kusuhara
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo, Japan
| | - Yoh Zen
- Institute of Liver Studies, King's College Hospital & King's College London, London, UK
| | - Tomohiro Ando
- Axcelead Drug Discovery Partners, Inc., Fujisawa, Kanagawa, Japan
| | - Hisamitsu Hayashi
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo, Japan.
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13
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Maury EA, Sherman MA, Genovese G, Gilgenast TG, Kamath T, Burris S, Rajarajan P, Flaherty E, Akbarian S, Chess A, McCarroll SA, Loh PR, Phillips-Cremins JE, Brennand KJ, Macosko EZ, Walters JT, O’Donovan M, Sullivan P, Sebat J, Lee EA, Walsh CA. Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions. CELL GENOMICS 2023; 3:100356. [PMID: 37601975 PMCID: PMC10435376 DOI: 10.1016/j.xgen.2023.100356] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 02/21/2022] [Accepted: 06/09/2023] [Indexed: 08/22/2023]
Abstract
While germline copy-number variants (CNVs) contribute to schizophrenia (SCZ) risk, the contribution of somatic CNVs (sCNVs)-present in some but not all cells-remains unknown. We identified sCNVs using blood-derived genotype arrays from 12,834 SCZ cases and 11,648 controls, filtering sCNVs at loci recurrently mutated in clonal blood disorders. Likely early-developmental sCNVs were more common in cases (0.91%) than controls (0.51%, p = 2.68e-4), with recurrent somatic deletions of exons 1-5 of the NRXN1 gene in five SCZ cases. Hi-C maps revealed ectopic, allele-specific loops forming between a potential cryptic promoter and non-coding cis-regulatory elements upon 5' deletions in NRXN1. We also observed recurrent intragenic deletions of ABCB11, encoding a transporter implicated in anti-psychotic response, in five treatment-resistant SCZ cases and showed that ABCB11 is specifically enriched in neurons forming mesocortical and mesolimbic dopaminergic projections. Our results indicate potential roles of sCNVs in SCZ risk.
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Affiliation(s)
- Eduardo A. Maury
- Division of Genetics and Genomics, Manton Center for Orphan Disease, Boston Children’s Hospital, Boston, MA, USA
- Bioinformatics & Integrative Genomics Program and Harvard/MIT MD-PHD Program, Harvard Medical School, Boston, MA, USA
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Maxwell A. Sherman
- Brigham and Women’s Hospital, Division of Genetics & Center for Data Sciences, Boston, MA, USA
| | - Giulio Genovese
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Genetics, Harvard Medical School, Boston, MA, USA
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Thomas G. Gilgenast
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA
| | - Tushar Kamath
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Harvard Graduate Program in Biophysics, Harvard University, Cambridge, MA, USA
| | - S.J. Burris
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Prashanth Rajarajan
- Nash Family Department of Neuroscience, Friedman Brain Institute, Department of Genetics & Genomics, Icahn Institute of Genomics and Multiscale Biology, Department of Psychiatry, Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine of Mount Sinai, New York, NY, USA
| | - Erin Flaherty
- Nash Family Department of Neuroscience, Friedman Brain Institute, Department of Genetics & Genomics, Icahn Institute of Genomics and Multiscale Biology, Department of Psychiatry, Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine of Mount Sinai, New York, NY, USA
| | - Schahram Akbarian
- Nash Family Department of Neuroscience, Friedman Brain Institute, Department of Genetics & Genomics, Icahn Institute of Genomics and Multiscale Biology, Department of Psychiatry, Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine of Mount Sinai, New York, NY, USA
| | - Andrew Chess
- Nash Family Department of Neuroscience, Friedman Brain Institute, Department of Genetics & Genomics, Icahn Institute of Genomics and Multiscale Biology, Department of Psychiatry, Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine of Mount Sinai, New York, NY, USA
| | - Steven A. McCarroll
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Genetics, Harvard Medical School, Boston, MA, USA
| | - Po-Ru Loh
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Brigham and Women’s Hospital, Division of Genetics & Center for Data Sciences, Boston, MA, USA
| | | | - Kristen J. Brennand
- Nash Family Department of Neuroscience, Friedman Brain Institute, Department of Genetics & Genomics, Icahn Institute of Genomics and Multiscale Biology, Department of Psychiatry, Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine of Mount Sinai, New York, NY, USA
- Departments of Psychiatry and Genetics, Yale School of Medicine, New Haven, CT, USA
| | - Evan Z. Macosko
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Massachusetts General Hospital, Department of Psychiatry, Boston, MA, USA
| | - James T.R. Walters
- MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychiatry and Clinical Neurosciences, Cardiff University, Cardiff, Wales
| | - Michael O’Donovan
- MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychiatry and Clinical Neurosciences, Cardiff University, Cardiff, Wales
| | - Patrick Sullivan
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Jonathan Sebat
- University of California San Diego, Department of Psychiatry, Department of Cellular & Molecular Medicine, Beyster Center of Psychiatric Genomics, San Diego, CA, USA
| | - Eunjung A. Lee
- Division of Genetics and Genomics, Manton Center for Orphan Disease, Boston Children’s Hospital, Boston, MA, USA
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Christopher A. Walsh
- Division of Genetics and Genomics, Manton Center for Orphan Disease, Boston Children’s Hospital, Boston, MA, USA
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Howard Hughes Medical Institute, Boston Children’s Hospital, Boston, MA, USA
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14
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Gupta K. A modular analysis of bile canalicular function and its implications for cholestasis. Am J Physiol Gastrointest Liver Physiol 2023; 325:G14-G22. [PMID: 37192193 PMCID: PMC10259850 DOI: 10.1152/ajpgi.00165.2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 05/03/2023] [Accepted: 05/11/2023] [Indexed: 05/18/2023]
Abstract
Hepatocytes produce bile components and secrete them into a lumen, known as a bile canaliculus, that is formed by the apical membranes of adjoining hepatocytes. Bile canaliculi merge to form tubular structures that subsequently connect to the canal of Hering and larger intra- and extrahepatic bile ducts formed by cholangiocytes, which modify bile and enable flow through the small intestine. The major functional requirements for bile canaliculi are the maintenance of canalicular shape to preserve the blood-bile barrier and regulation of bile flow. These functional requirements are mediated by functional modules, primarily transporters, the cytoskeleton, cell-cell junctions, and mechanosensing proteins. I propose here that bile canaliculi behave as robust machines whereby the functional modules act in a coordinated manner to perform the multistep task of maintaining canalicular shape and bile flow. Cholestasis, the general term for aberrant bile flow, stems from drug/toxin-induced or genetic dysregulation of one or more of the protein components in the functional modules. Here, I discuss the interactions between components of the various functional modules in bile canaliculi and describe how these functional modules regulate canalicular morphology and function. I use this framework to provide a perspective on recent studies of bile canalicular dynamics.
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Affiliation(s)
- Kapish Gupta
- Division of Gastroenterology and Hepatology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Center for Engineering MechanoBiology, The University of Pennsylvania, Philadelphia, Pennsylvania, United States
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15
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Zhu F, Zheng S, Zhao M, Shi F, Zheng L, Wang H. The regulatory role of bile acid microbiota in the progression of liver cirrhosis. Front Pharmacol 2023; 14:1214685. [PMID: 37416060 PMCID: PMC10320161 DOI: 10.3389/fphar.2023.1214685] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Accepted: 06/12/2023] [Indexed: 07/08/2023] Open
Abstract
Bile acids (BAs) are synthesized in liver tissue from cholesterol and are an important endocrine regulator and signaling molecule in the liver and intestine. It maintains BAs homeostasis, and the integrity of intestinal barrier function, and regulates enterohepatic circulation in vivo by modulating farnesoid X receptors (FXR) and membrane receptors. Cirrhosis and its associated complications can lead to changes in the composition of intestinal micro-ecosystem, resulting in dysbiosis of the intestinal microbiota. These changes may be related to the altered composition of BAs. The BAs transported to the intestinal cavity through the enterohepatic circulation are hydrolyzed and oxidized by intestinal microorganisms, resulting in changes in their physicochemical properties, which can also lead to dysbiosis of intestinal microbiota and overgrowth of pathogenic bacteria, induction of inflammation, and damage to the intestinal barrier, thus aggravating the progression of cirrhosis. In this paper, we review the discussion of BAs synthesis pathway and signal transduction, the bidirectional regulation of bile acids and intestinal microbiota, and further explore the role of reduced total bile acid concentration and dysregulated intestinal microbiota ratio in the development of cirrhosis, in order to provide a new theoretical basis for the clinical treatment of cirrhosis and its complications.
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Affiliation(s)
- Feng Zhu
- Heilongjiang University of Chinese Medicine, Harbin, China
| | - Shudan Zheng
- First Clinical School of Medicine, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Mei Zhao
- First Clinical School of Medicine, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Fan Shi
- First Clinical School of Medicine, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Lihong Zheng
- Department of Gastroenterology, Fourth Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Haiqiang Wang
- Department of Gastroenterology, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China
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16
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Lipiński P, Ciara E, Jurkiewicz D, Płoski R, Wawrzynowicz-Syczewska M, Pawłowska J, Jankowska I. Progressive familial intrahepatic cholestasis type 3: Report of four clinical cases, novel ABCB4 variants and long-term follow-up. Ann Hepatol 2022; 25:100342. [PMID: 33757843 DOI: 10.1016/j.aohep.2021.100342] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 02/24/2021] [Accepted: 03/03/2021] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND OBJECTIVES Progressive familial intrahepatic cholestasis type 3 (PFIC-3) is a rare autosomal recessive cholestatic liver disorder caused by mutations in the ABCB4 gene. The aim of this study was to present the phenotypic and genotypic spectrum of 4 Polish PFIC-3 patients diagnosed in a one-referral centre. MATERIALS AND METHODS The study included 4 patients with cholestasis and pathogenic variants in the ABCB4 gene identified by next-generation sequencing (NGS) of a targeted-gene panel or whole exome sequencing (WES). Clinical, laboratory, histological, and molecular data were collected. RESULTS Four patients (three males) were identified. The age at first noted clinical signs and symptoms was 6, 2.5, 14, and 2 years respectively; the mean age was 6 years. Those signs and symptoms include pruritus (2 out of 4 patients) and hepatomegaly with splenomegaly (4 out of 4 patients). The age at the time of referral to our centre was 9, 3, 15, and 2.5 years respectively, while the mean age was 7 years. Chronic cholestatic liver disease of unknown aetiology was established in all of them. The NGS analysis was performed in all patients at the last follow-up visit. Three novel variants including c.902T>A, p.Met301Lys, c.3279+1G>A, p.?, and c.3524T>A, p.Leu1175His were identified. The time from the first consultation to the final diagnosis was 14, 9, 3, and 1 year respectively; the mean was 6.8 years. A detailed follow-up was presented. CONCLUSIONS The clinical phenotype of PFIC-3 could be variable. The clinical and biochemical diagnosis of PFIC-3 is difficult, thus the NGS study is very useful in making a proper diagnosis.
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Affiliation(s)
- Patryk Lipiński
- Department of Pediatrics, Nutrition and Metabolic Diseases, The Children's Memorial Health Institute, Warsaw, Poland; Department of Gastroenterology, Hepatology, Nutritional Disturbances and Pediatrics, Children's Memorial Health Institute, Warsaw, Poland.
| | - Elżbieta Ciara
- Department of Medical Genetics, The Children's Memorial Health Institute, Warsaw, Poland
| | - Dorota Jurkiewicz
- Department of Medical Genetics, The Children's Memorial Health Institute, Warsaw, Poland
| | - Rafał Płoski
- Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland
| | - Marta Wawrzynowicz-Syczewska
- Department of Infectious Diseases, Hepatology and Liver Transplantation, Pomeranian Medical University in Szczecin, Poland
| | - Joanna Pawłowska
- Department of Gastroenterology, Hepatology, Nutritional Disturbances and Pediatrics, Children's Memorial Health Institute, Warsaw, Poland
| | - Irena Jankowska
- Department of Gastroenterology, Hepatology, Nutritional Disturbances and Pediatrics, Children's Memorial Health Institute, Warsaw, Poland
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17
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Environmental and Lifestyle Risk Factors in the Carcinogenesis of Gallbladder Cancer. J Pers Med 2022; 12:jpm12020234. [PMID: 35207722 PMCID: PMC8877116 DOI: 10.3390/jpm12020234] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Revised: 11/08/2021] [Accepted: 12/23/2021] [Indexed: 02/01/2023] Open
Abstract
Gallbladder cancer (GBC) is an aggressive neoplasm that in an early stage is generally asymptomatic and, in most cases, is diagnosed in advanced stages with a very low life expectancy because there is no curative treatment. Therefore, understanding the early carcinogenic mechanisms of this pathology is crucial to proposing preventive strategies for this cancer. The main risk factor is the presence of gallstones, which are associated with some environmental factors such as a sedentary lifestyle and a high-fat diet. Other risk factors such as autoimmune disorders and bacterial, parasitic and fungal infections have also been described. All these factors can generate a long-term inflammatory state characterized by the persistent activation of the immune system, the frequent release of pro-inflammatory cytokines, and the constant production of reactive oxygen species that result in a chronic damage/repair cycle, subsequently inducing the loss of the normal architecture of the gallbladder mucosa that leads to the development of GBC. This review addresses how the different risk factors could promote a chronic inflammatory state essential to the development of gallbladder carcinogenesis, which will make it possible to define some strategies such as anti-inflammatory drugs or public health proposals in the prevention of GBC.
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18
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Masahata K, Ueno T, Bessho K, Kodama T, Tsukada R, Saka R, Tazuke Y, Miyagawa S, Okuyama H. Clinical outcomes of surgical management for rare types of progressive familial intrahepatic cholestasis: a case series. Surg Case Rep 2022; 8:10. [PMID: 35024979 PMCID: PMC8758805 DOI: 10.1186/s40792-022-01365-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 01/10/2022] [Indexed: 12/14/2022] Open
Abstract
Background Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of genetic autosomal recessive diseases that cause severe cholestasis, which progresses to cirrhosis and liver failure, in infancy or early childhood. We herein report the clinical outcomes of surgical management in patients with four types of PFIC. Case presentation Six patients diagnosed with PFIC who underwent surgical treatment between 1998 and 2020 at our institution were retrospectively assessed. Living-donor liver transplantation (LDLT) was performed in 5 patients with PFIC. The median age at LDLT was 4.8 (range: 1.9–11.4) years. One patient each with familial intrahepatic cholestasis 1 (FIC1) deficiency and bile salt export pump (BSEP) deficiency died after LDLT, and the four remaining patients, one each with deficiency of FIC1, BSEP, multidrug resistance protein 3 (MDR3), and tight junction protein 2 (TJP2), survived. One FIC1 deficiency recipient underwent LDLT secondary to deterioration of liver function, following infectious enteritis. Although he underwent LDLT accompanied by total external biliary diversion, the patient died because of PFIC-related complications. The other patient with FIC1 deficiency had intractable pruritus and underwent partial internal biliary diversion (PIBD) at 9.8 years of age, pruritus largely resolved after PIBD. One BSEP deficiency recipient, who had severe graft damage, experienced recurrence of cholestasis due to the development of antibodies against BSEP after LDLT, and eventually died due to graft failure. The other patient with BSEP deficiency recovered well after LDLT and there was no evidence of posttransplant recurrence of cholestasis. In contrast, recipients with MDR3 or TJP2 deficiency showed good courses and outcomes after LDLT. Conclusions Although LDLT was considered an effective treatment for PFIC, the clinical courses and outcomes after LDLT were still inadequate in patients with FIC1 and BSEP deficiency. LDLT accompanied by total biliary diversion may not be as effective for patients with FIC1 deficiency.
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Affiliation(s)
- Kazunori Masahata
- Department of Pediatric Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Takehisa Ueno
- Department of Pediatric Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
| | - Kazuhiko Bessho
- Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Tasuku Kodama
- Department of Pediatric Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Ryo Tsukada
- Department of Pediatric Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Ryuta Saka
- Department of Pediatric Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Yuko Tazuke
- Department of Pediatric Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Shuji Miyagawa
- Department of Pediatric Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Hiroomi Okuyama
- Department of Pediatric Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
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19
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Abstract
Bile acids and their signaling pathways are increasingly recognized as potential therapeutic targets for cholestatic and metabolic liver diseases. This review summarizes new insights in bile acid physiology, focusing on regulatory roles of bile acids in the control of immune regulation and on effects of pharmacological modulators of bile acid signaling pathways in human liver disease. Recent mouse studies have highlighted the importance of the interactions between bile acids and gut microbiome. Interfering with microbiome composition may be beneficial for cholestatic and metabolic liver diseases by modulating formation of secondary bile acids, as different bile acid species have different signaling functions. Bile acid receptors such as FXR, VDR, and TGR5 are expressed in a variety of cells involved in innate as well as adaptive immunity, and specific microbial bile acid metabolites positively modulate immune responses of the host. Identification of Cyp2c70 as the enzyme responsible for the generation of hydrophilic mouse/rat-specific muricholic acids has allowed the generation of murine models with a human-like bile acid composition. These novel mouse models will aid to accelerate translational research on the (patho)physiological roles of bile acids in human liver diseases .
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20
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Stellaard F, Lütjohann D. Dynamics of the enterohepatic circulation of bile acids in healthy humans. Am J Physiol Gastrointest Liver Physiol 2021; 321:G55-G66. [PMID: 33978477 DOI: 10.1152/ajpgi.00476.2020] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Regulation of bile acid metabolism is normally discussed as the regulation of bile acid synthesis, which serves to compensate for intestinal loss in order to maintain a constant pool size. After a meal, bile acids start cycling in the enterohepatic circulation. Farnesoid X receptor-dependent ileal and hepatic processes lead to negative feedback inhibition of bile acid synthesis. When the intestinal bile acid flux decreases, the inhibition of synthesis is released. The degree of inhibition of synthesis and the mechanism and degree of activation are still unknown. Moreover, in humans, a biphasic diurnal expression pattern of bile acid synthesis has been documented, indicating maximal synthesis around 3 PM and 9 PM. Quantitative data on the hourly synthesis schedule as compensation for intestinal loss are lacking. In this review, we describe the classical view on bile acid metabolism and present alternative concepts that are based on the overlooked feature that bile acids transit through the enterohepatic circulation very rapidly. A daily profile of the cycling and total bile acid pool sizes and potential controlled and uncontrolled mechanisms for synthesis are predicted. It remains to be elucidated by which mechanism clock genes interact with the Farnesoid X receptor-controlled regulation of bile acid synthesis. This mechanism could become an attractive target to enhance bile acid synthesis at night, when cholesterol synthesis is high, thus lowering serum LDL-cholesterol.
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Affiliation(s)
- Frans Stellaard
- Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Venusberg-Campus 1, Bonn, Germany
| | - Dieter Lütjohann
- Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Venusberg-Campus 1, Bonn, Germany
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21
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Alamoudi JA, Li W, Gautam N, Olivera M, Meza J, Mukherjee S, Alnouti Y. Bile acid indices as biomarkers for liver diseases I: Diagnostic markers. World J Hepatol 2021; 13:433-455. [PMID: 33959226 PMCID: PMC8080550 DOI: 10.4254/wjh.v13.i4.433] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 02/11/2021] [Accepted: 03/22/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatobiliary diseases result in the accumulation of toxic bile acids (BA) in the liver, blood, and other tissues which may contribute to an unfavorable prognosis. AIM To discover and validate diagnostic biomarkers of cholestatic liver diseases based on the urinary BA profile. METHODS We analyzed urine samples by liquid chromatography-tandem mass spectrometry and compared the urinary BA profile between 300 patients with hepatobiliary diseases vs 103 healthy controls by statistical analysis. The BA profile was characterized using BA indices, which quantifies the composition, metabolism, hydrophilicity, and toxicity of the BA profile. BA indices have much lower inter- and intra-individual variability compared to absolute concentrations of BA. In addition, BA indices demonstrate high area under the receiver operating characteristic curves, and changes of BA indices are associated with the risk of having a liver disease, which demonstrates their use as diagnostic biomarkers for cholestatic liver diseases. RESULTS Total and individual BA concentrations were higher in all patients. The percentage of secondary BA (lithocholic acid and deoxycholic acid) was significantly lower, while the percentage of primary BA (chenodeoxycholic acid, cholic acid, and hyocholic acid) was markedly higher in patients compared to controls. In addition, the percentage of taurine-amidation was higher in patients than controls. The increase in the non-12α-OH BA was more profound than 12α-OH BA (cholic acid and deoxycholic acid) causing a decrease in the 12α-OH/ non-12α-OH ratio in patients. This trend was stronger in patients with more advanced liver diseases as reflected by the model for end-stage liver disease score and the presence of hepatic decompensation. The percentage of sulfation was also higher in patients with more severe forms of liver diseases. CONCLUSION BA indices have much lower inter- and intra-individual variability compared to absolute BA concentrations and changes of BA indices are associated with the risk of developing liver diseases.
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Affiliation(s)
- Jawaher Abdullah Alamoudi
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Wenkuan Li
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Nagsen Gautam
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Marco Olivera
- Department of Internal Medicine, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Jane Meza
- Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Sandeep Mukherjee
- Department of Internal Medicine, College of Medicine, Creighton University Medical Center, Omaha, NE 68124, United States
| | - Yazen Alnouti
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, United States.
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22
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Hayashi H, Osaka S, Sakabe K, Fukami A, Kishimoto E, Aihara E, Sabu Y, Mizutani A, Kusuhara H, Naritaka N, Zhang W, Huppert SS, Sakabe M, Nakamura T, Hu YC, Mayhew C, Setchell K, Takebe T, Asai A. Modeling Human Bile Acid Transport and Synthesis in Stem Cell-Derived Hepatocytes with a Patient-Specific Mutation. Stem Cell Reports 2021; 16:309-323. [PMID: 33450190 PMCID: PMC7878720 DOI: 10.1016/j.stemcr.2020.12.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 12/13/2020] [Accepted: 12/14/2020] [Indexed: 01/13/2023] Open
Abstract
The bile salt export pump (BSEP) is responsible for the export of bile acid from hepatocytes. Impaired transcellular transport of bile acids in hepatocytes with mutations in BSEP causes cholestasis. Compensatory mechanisms to regulate the intracellular bile acid concentration in human hepatocytes with BSEP deficiency remain unclear. To define pathways that prevent cytotoxic accumulation of bile acid in hepatocytes, we developed a human induced pluripotent stem cell-based model of isogenic BSEP-deficient hepatocytes in a Transwell culture system. Induced hepatocytes (i-Heps) exhibited defects in the apical export of bile acids but maintained a low intracellular bile acid concentration by inducing basolateral export. Modeling the autoregulation of bile acids on hepatocytes, we found that BSEP-deficient i-Heps suppressed de novo bile acid synthesis using the FXR pathway via basolateral uptake and export without apical export. These observations inform the development of therapeutic targets to reduce the overall bile acid pool in patients with BSEP deficiency.
Human isogenic iPSCs were generated by CRISPR to study a truncating mutation of BSEP iPSC-derived hepatocytes recapitulate pathophysiology of BSEP deficiency in patients BSEP-deficient hepatocytes induce alternative basolateral bile acid export Activation of FXR suppresses de novo bile acid synthesis in BSEP-deficient hepatocytes
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Affiliation(s)
- Hisamitsu Hayashi
- Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo, Japan
| | - Shuhei Osaka
- Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo, Japan
| | - Kokoro Sakabe
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Aiko Fukami
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Eriko Kishimoto
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Eitaro Aihara
- College of Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Yusuke Sabu
- Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo, Japan
| | - Ayumu Mizutani
- Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo, Japan
| | - Hiroyuki Kusuhara
- Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo, Japan
| | | | - Wujuan Zhang
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; College of Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Stacey S Huppert
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; College of Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Masahide Sakabe
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Takahisa Nakamura
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; College of Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Yueh-Chiang Hu
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; College of Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Christopher Mayhew
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; College of Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Kenneth Setchell
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; College of Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Takanori Takebe
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; College of Medicine, University of Cincinnati, Cincinnati, OH, USA; Institute of Research, Tokyo Medical and Dental University, Tokyo, Japan
| | - Akihiro Asai
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
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23
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Wei X, Ma Y, Dong Z, Wang G, Lan X, Liao Z, Chen M. Dehydrodiconiferyl alcohol, a lignan from Herpetospermum pedunculosum, alleviates cholestasis by activating pathways associated with the farnesoid X receptor. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2021; 80:153378. [PMID: 33113499 DOI: 10.1016/j.phymed.2020.153378] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 09/07/2020] [Accepted: 10/11/2020] [Indexed: 06/11/2023]
Abstract
BACKGROUND In our previous study, we demonstrated the hepatoprotective effect of Herpetospermum pedunculosum in cholestatic rats. A bioassay-guided study also led to the identification and isolation of a lignan, dihydrodiconiferyl alcohol (DA) from the seeds of H. pedunculosum. PURPOSE To investigate whether DA could alleviate cholestasis and determine the mechanisms underlying such action. METHODS Male Sprague-Dawley (SD) rats were administered with DA (10, 20 or 40 mg/kg) intragastrically once daily for 7 days prior to treatment with α-naphthylisothiocyanate (ANIT) (60 mg/kg). We then evaluated the levels of a range of serum indicators, determined bile flow, and carried out histopathological analyses. Western blotting was then used to investigate the levels of inflammatory mediators and the Farnesoid X Receptor (FXR), proteins involved in the downstream biosynthesis of bile acids, and a range of transport proteins. Molecular docking was used to simulate the interaction between DA and FXR. Cell viability of human hepatocytes (L-02) cells was determined by MTT. Then, we treated guggulsterone-inhibited L-02 cells, Si-FXR L-02 cells, and FXR-overexpression cells with the FXR agonist GW4064 (6 μM) or DA (25, 50 and 100 μM) for 24 h before detecting gene and protein expression by RT-PCR and western blotting, respectively. RESULTS DA significantly attenuated ANIT-induced cholestasis in SD rats by reducing liver function indicators in the serum, increasing bile flow, improving the recovery of histopathological injuries in the liver, and by alleviating pro-inflammatory cytokines in the liver. DA also increased the expression levels of FXR and altered the levels of downstream proteins in the liver tissues, thus indicating that DA might alleviate cholestasis by regulating the FXR. Molecular docking simulations predicted that DA was as an agonist of FXR. In vitro mechanical studies further showed that DA increased the mRNA and protein expression levels of FXR, Small Heterodimer Partner 1/2, Bile Salt Export Pump, Multidrug Resistance-associated Protein 2, and Na+/taurocholate Co-transporting Polypeptide, in both guggulsterone-inhibited and Si-FXR L-02 cells. Moreover, DA enhanced the mRNA and protein expression of FXR, and its downstream genes and proteins, in L-02 cells containing an FXR-overexpression plasmid. CONCLUSION DA may represent an effective agonist for FXR has significant therapeutic potential for the treatment of cholestatic liver injury.
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MESH Headings
- 1-Naphthylisothiocyanate/toxicity
- ATP Binding Cassette Transporter, Subfamily B, Member 11/metabolism
- Animals
- Bile/metabolism
- Bile Acids and Salts/metabolism
- Cholestasis, Intrahepatic/chemically induced
- Cholestasis, Intrahepatic/drug therapy
- Cholestasis, Intrahepatic/metabolism
- Cholestasis, Intrahepatic/pathology
- Cucurbitaceae/chemistry
- Hepatocytes/drug effects
- Humans
- Isoxazoles/pharmacology
- Liver/drug effects
- Liver/metabolism
- Liver/pathology
- Male
- Molecular Docking Simulation
- Phenols/chemistry
- Phenols/pharmacology
- Rats, Sprague-Dawley
- Receptors, Cytoplasmic and Nuclear/agonists
- Receptors, Cytoplasmic and Nuclear/chemistry
- Receptors, Cytoplasmic and Nuclear/genetics
- Receptors, Cytoplasmic and Nuclear/metabolism
- Rats
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Affiliation(s)
- Xiaodong Wei
- College of Pharmaceutical Sciences, Southwest University, No.2 Tiansheng Road, Chongqing 400715, PR China
| | - Yingxiong Ma
- College of Pharmaceutical Sciences, Southwest University, No.2 Tiansheng Road, Chongqing 400715, PR China
| | - Zhaoyue Dong
- College of Pharmaceutical Sciences, Southwest University, No.2 Tiansheng Road, Chongqing 400715, PR China
| | - Guowei Wang
- College of Pharmaceutical Sciences, Southwest University, No.2 Tiansheng Road, Chongqing 400715, PR China
| | - Xiaozhong Lan
- TAAHC-SWU Medicinal Plant R&D Center, Xizang Agriculture and Animal Husbandry College, Nyingchi, Tibet, PR China
| | - Zhihua Liao
- School of Life Sciences, Southwest University, Chongqing 400715, PR China
| | - Min Chen
- College of Pharmaceutical Sciences, Southwest University, No.2 Tiansheng Road, Chongqing 400715, PR China.
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24
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Kroll T, Prescher M, Smits SHJ, Schmitt L. Structure and Function of Hepatobiliary ATP Binding Cassette Transporters. Chem Rev 2020; 121:5240-5288. [PMID: 33201677 DOI: 10.1021/acs.chemrev.0c00659] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The liver is beyond any doubt the most important metabolic organ of the human body. This function requires an intensive crosstalk within liver cellular structures, but also with other organs. Membrane transport proteins are therefore of upmost importance as they represent the sensors and mediators that shuttle signals from outside to the inside of liver cells and/or vice versa. In this review, we summarize the known literature of liver transport proteins with a clear emphasis on functional and structural information on ATP binding cassette (ABC) transporters, which are expressed in the human liver. These primary active membrane transporters form one of the largest families of membrane proteins. In the liver, they play an essential role in for example bile formation or xenobiotic export. Our review provides a state of the art and comprehensive summary of the current knowledge of hepatobiliary ABC transporters. Clearly, our knowledge has improved with a breath-taking speed over the last few years and will expand further. Thus, this review will provide the status quo and will lay the foundation for new and exciting avenues in liver membrane transporter research.
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Affiliation(s)
- Tim Kroll
- Institute of Biochemistry, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany
| | - Martin Prescher
- Institute of Biochemistry, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany
| | - Sander H J Smits
- Institute of Biochemistry, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany.,Center for Structural Studies, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany
| | - Lutz Schmitt
- Institute of Biochemistry, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany
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25
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Li LT, Li ZD, Yang Y, Lu Y, Xie XB, Chen L, Feng JY, Knisely AS, Wang JS. ABCB11 deficiency presenting as transient neonatal cholestasis: Correlation with genotypes and BSEP expression. Liver Int 2020; 40:2788-2796. [PMID: 32808743 DOI: 10.1111/liv.14642] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Revised: 08/10/2020] [Accepted: 08/13/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS ABCB11 deficiency presenting in infancy is believed generally to manifest as persistent/progressive cholestasis. We describe a group of patients with biallelic ABCB11 variants whose disorder manifested as transient neonatal cholestasis (TNC). METHODS Neonatal intrahepatic cholestasis in 68 children (31 males) with biallelic predictedly pathogenic variants (PPV) in ABCB11 was classified as transient (TNC group, n = 23, 11 males), intermittent (benign recurrent intrahepatic cholestasis [BRIC] group, n = 3, 1 male) or persistent/ progressive (progressive familial intrahepatic cholestasis [PFIC] group, n = 42, 19 males). Clinical, genetic and bile salt export pump (BSEP) expression information was correlated with outcomes. RESULTS The median onset age of jaundice was 3 days (birth to 2 months) for the TNC group and 10.5 days (birth to 3 months) for the PFIC group (P = .034). The median length of follow-up of TNC patients was 44 months (12 months-168 months). At presentation, hepatobiliary-injury biomarker values were similar between the groups (P > .05). TNC patients (17/23) more often than PFIC patients (20/42, P = .041) harboured biallelic non-null variants (predicted not to terminate translation prematurely). TNC patient livers (7/7) more often than PFIC patient livers (5/16, P = .005) expressed immunohistochemically detectable BSEP. Kaplan-Meier analysis showed better prognosis for patients with BSEP expression (P = .009). Too few BRIC patients were available for statistical study. CONCLUSIONS Neonatal cholestasis associated with biallelic PPV in ABCB11 can resolve temporarily or persistently in one third of cases. Resolution is more likely in patients with biallelic non-null PPV or with liver BSEP expression.
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Affiliation(s)
- Li-Ting Li
- The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, Shanghai, China
| | - Zhong-Die Li
- The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, Shanghai, China
| | - Ye Yang
- Department of Pediatrics, Jinshan Hospital, Fudan University, Shanghai, China
| | - Yi Lu
- The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, Shanghai, China
| | - Xin-Bao Xie
- The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, Shanghai, China
| | - Lian Chen
- Department of Pathology, Children's Hospital of Fudan University, Shanghai, China
| | - Jia-Yan Feng
- Department of Pathology, Children's Hospital of Fudan University, Shanghai, China
| | - A S Knisely
- Institut für Pathologie, Medizinische Universität Graz, Graz, Austria
| | - Jian-She Wang
- The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, Shanghai, China.,Shanghai Key Laboratory of Birth Defects, Shanghai, China
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26
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Scott NA, Sharpe LJ, Brown AJ. The E3 ubiquitin ligase MARCHF6 as a metabolic integrator in cholesterol synthesis and beyond. Biochim Biophys Acta Mol Cell Biol Lipids 2020; 1866:158837. [PMID: 33049405 DOI: 10.1016/j.bbalip.2020.158837] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 09/29/2020] [Accepted: 10/02/2020] [Indexed: 12/19/2022]
Abstract
MARCHF6 is a large multi-pass E3 ubiquitin ligase embedded in the membranes of the endoplasmic reticulum. It participates in endoplasmic reticulum associated degradation, including autoubiquitination, and many of its identified substrates are involved in sterol and lipid metabolism. Post-translationally, MARCHF6 expression is attuned to cholesterol status, with high cholesterol preventing its degradation and hence boosting MARCHF6 levels. By modulating MARCHF6 activity, cholesterol may regulate other aspects of cell metabolism beyond the known repertoire. Whilst we have learnt much about MARCHF6 in the past decade, there are still many more mysteries to be unravelled to fully understand its regulation, substrates, and role in human health and disease.
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Affiliation(s)
- Nicola A Scott
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia
| | - Laura J Sharpe
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia
| | - Andrew J Brown
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia.
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27
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Nasobiliary drainage prior to surgical biliary diversion in progressive familial intrahepatic cholestasis type II. Eur J Pediatr 2020; 179:1547-1552. [PMID: 32291498 DOI: 10.1007/s00431-020-03646-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Revised: 03/18/2020] [Accepted: 03/27/2020] [Indexed: 12/12/2022]
Abstract
Progressive familial intrahepatic cholestasis (PFIC) can cause intense pruritus that is refractory to medical therapy. Surgical biliary diversion techniques, including partial internal biliary diversion (PIBD), have been developed over the years to relieve pruritus without requiring liver transplantation. No clinical or genetic features can currently predict postoperative pruritus response. We present three PFIC type 2 (PIFC 2) patients who underwent transient endoscopic nasobiliary drainage (NBD) prior to PIBD surgery. Two patients repeatedly responded to NBD and presented with complete pruritus resolution after subsequent PIBD. NBD failed technically in the third patient, and PIBD was partially successful. Mild post-endoscopic biological pancreatitis occurred in 2/6 NBD procedures and resolved spontaneously. The only adverse effect observed within 7 years post-PIBD was very mild transient osmotic diarrhea.Conclusion: Our limited data suggest that NBD is a safe and effective way to predict pruritus response before performing permanent biliary diversion surgery in PFIC patients. What is Known: • Surgical biliary diversion techniques have been developed to relieve intractable pruritus in progressive familial intrahepatic cholestasis (PFIC). • No clinical or genetic features can currently predict pruritus response to surgery. What is New: • Our data suggest that nasobiliary drainage could be a safe and effective tool to predict pruritus response to biliary diversion and avoid unnecessary surgery in PFIC patients.
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28
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Slavetinsky C, Sturm E. Odevixibat and partial external biliary diversion showed equal improvement of cholestasis in a patient with progressive familial intrahepatic cholestasis. BMJ Case Rep 2020; 13:13/6/e234185. [PMID: 32601135 PMCID: PMC7326258 DOI: 10.1136/bcr-2019-234185] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Untreated progressive familial intrahepatic cholestasis (PFIC) type 2, or bile salt exporter protein deficiency, frequently leads to severe pruritus, impaired growth and progressive liver fibrosis with risk of organ failure. We describe a 15-month-old male patient with severe pruritus diagnosed with PFIC type 2 enrolled in an open-label phase 2 study who received 4 weeks of treatment with odevixibat, an ileal bile acid transporter inhibitor under development for cholestatic liver disease treatment. The patient experienced reductions in serum bile acids and improvement in itching and sleep scores, and odevixibat was well tolerated. After the odevixibat study, symptoms returned and the patient underwent partial external biliary diversion (PEBD). Odevixibat treatment and PEBD produced similar normalisation of serum bile acid levels and improvements in pruritus and sleep disruptions. Thus, odevixibat appeared to be as effective as invasive PEBD in treating serum bile acids and cholestatic pruritus in this patient.
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Affiliation(s)
- Christoph Slavetinsky
- Paediatric Gastroenterology and Hepatology, University Children's Hospital, Eberhard Karls University Tubingen, Tubingen, Germany
| | - Ekkehard Sturm
- Paediatric Gastroenterology and Hepatology, University Children's Hospital, Eberhard Karls University Tubingen, Tubingen, Germany
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29
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Mitra S, Das A, Thapa B, Kumar Vasishta R. Phenotype-Genotype Correlation of North Indian Progressive Familial Intrahepatic Cholestasis type2 Children Shows p.Val444Ala and p.Asn591Ser Variants and Retained BSEP Expression. Fetal Pediatr Pathol 2020; 39:107-123. [PMID: 31335238 DOI: 10.1080/15513815.2019.1641860] [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: 10/26/2022]
Abstract
Backgrounds and Aims: Progressive familial intrahepatic cholestasis type 2 (PFIC2) is caused by a defect or deficiency of bile salt export protein (BSEP) due to mutation in the ABCB11 gene. We intend to evaluate the phenotype-genotype correlation in 10 diagnosed cases of PFIC2 in a single tertiary care center in North India. Methods: The clinical, biochemical, histopathological, immunohistochemical, ultrastructural and genetic data of the 10 diagnosed cases of PFIC2 were recorded. Results: Icterus, pruritus and bleeding manifestations were the commonest clinical symptoms. Giant cell transformation was seen in 50% of the patients. Two predominant genetic variants were ABCB11 missense p.Val444Ala (c. 1331 T > C) and ABCB11 missense p.Asn591Ser (c. 1772 A > G) in their homozygous or compound heterozygous states and were associated with retained BSEP immunopositivity and reduced but retained BSEP immunopositivity respectively. Conclusion: Retention of BSEP is common in North Indian children of PFIC2 with no phenotype-genotype correlation.
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Affiliation(s)
| | - Ashim Das
- PGIMER, Histopathology, Chandigarh, India
| | - Baburam Thapa
- Post Graduate Institute of Medical Education and Research, Pediatric Gastroenterology, Nehru Hospital, Chandigarh, India
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30
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Quintero J, Juamperez J, Gonzales E, Julio E, Mercadal-Hally M, Collado-Hilly M, Marín-Sánchez A, Charco R. Successful Treatment with Rituximab and Immunoadsorption for an Auto-Antibody Induced Bile Salt Export Pump Deficiency in a Liver Transplanted Patient. Pediatr Gastroenterol Hepatol Nutr 2020; 23:174-179. [PMID: 32206630 PMCID: PMC7073374 DOI: 10.5223/pghn.2020.23.2.174] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Accepted: 12/12/2019] [Indexed: 12/11/2022] Open
Abstract
We present an 8 years old girl who was diagnosed at 6 months of age of Progressive Familial Intrahepatic Cholestasis type 2. Although liver transplantation (LT) was classically considered curative for these patients, cholestasis recurrence with normal gamma-glutamyl transpeptidase (GGT), mediated by anti-bile salt export pump (BSEP) antibodies after LT (auto-antibody Induced BSEP Deficiency, AIBD) has been recently reported. Our patient underwent LT at 14 months. During her evolution, patient presented three episodes of acute rejection. Seven years after the LT, the patient presented pruritus with cholestasis and elevation of liver enzymes with persistent normal GGT. Liver biopsy showed intrahepatic cholestasis and giant-cell transformation with very low BSEP activity. Auto-antibodies against BSEP were detected therefore an AIBD was diagnosed. She was treated with Rituximab and immunoadsorption with resolution of the AIBD. As a complication of the treatment she developed a pneumocystis infection successfully treated with corticoids, cotrimoxazol and anidulafungin.
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Affiliation(s)
- Jesús Quintero
- Pediatric Hepatology and Liver Transplantation Unit, Vall d'Hebron University Hospital, Universitat Autónoma de Barcelona, Barcelona, Spain
| | - Javier Juamperez
- Pediatric Hepatology and Liver Transplantation Unit, Vall d'Hebron University Hospital, Universitat Autónoma de Barcelona, Barcelona, Spain
| | - Emmanuel Gonzales
- Inserm Unité Mixte de Recherche 1193, Université Paris-Saclay, Orsay France
| | - Ecaterina Julio
- Pediatric Hepatology and Liver Transplantation Unit, Vall d'Hebron University Hospital, Universitat Autónoma de Barcelona, Barcelona, Spain
| | - Maria Mercadal-Hally
- Pediatric Hepatology and Liver Transplantation Unit, Vall d'Hebron University Hospital, Universitat Autónoma de Barcelona, Barcelona, Spain
| | | | - Ana Marín-Sánchez
- Department of Immunology, Vall d'Hebron University Hospital, Universitat Autónoma de Barcelona, Barcelona, Spain
| | - Ramon Charco
- Department of HPB Surgery and Trasplant, Vall d'Hebron University Hospital, Universitat Autónoma de Barcelona, Barcelona, Spain
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Garzel B, Zhang L, Huang SM, Wang H. A Change in Bile Flow: Looking Beyond Transporter Inhibition in the Development of Drug-induced Cholestasis. Curr Drug Metab 2020; 20:621-632. [PMID: 31288715 DOI: 10.2174/1389200220666190709170256] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 05/22/2019] [Accepted: 06/12/2019] [Indexed: 12/17/2022]
Abstract
BACKGROUND Drug-induced Liver Injury (DILI) has received increasing attention over the past decades, as it represents the leading cause of drug failure and attrition. One of the most prevalent and severe forms of DILI involves the toxic accumulation of bile acids in the liver, known as Drug-induced Cholestasis (DIC). Traditionally, DIC is studied by exploring the inhibition of hepatic transporters such as Bile Salt Export Pump (BSEP) and multidrug resistance-associated proteins, predominantly through vesicular transport assays. Although this approach has identified numerous drugs that alter bile flow, many DIC drugs do not demonstrate prototypical transporter inhibition, but rather are associated with alternative mechanisms. METHODS We undertook a focused literature search on DIC and biliary transporters and analyzed peer-reviewed publications over the past two decades or so. RESULTS We have summarized the current perception regarding DIC, biliary transporters, and transcriptional regulation of bile acid homeostasis. A growing body of literature aimed to identify alternative mechanisms in the development of DIC has been evaluated. This review also highlights current in vitro approaches used for prediction of DIC. CONCLUSION Efforts have continued to focus on BSEP, as it is the primary route for hepatic biliary clearance. In addition to inhibition, drug-induced BSEP repression or the combination of these two has emerged as important alternative mechanisms leading to DIC. Furthermore, there has been an evolution in the approaches to studying DIC including 3D cell cultures and computational modeling.
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Affiliation(s)
- Brandy Garzel
- Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration (FDA), Silver Spring, MD 20993, United States.,Becton Dickinson, 54 Loveton Circle, Sparks, MD 21152, United States
| | - Lei Zhang
- Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration (FDA), Silver Spring, MD 20993, United States.,Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, FDA, Silver Spring, MD 20993, United States
| | - Shiew-Mei Huang
- Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration (FDA), Silver Spring, MD 20993, United States
| | - Hongbing Wang
- Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, United States
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Ghanem CI, Manautou JE. Modulation of Hepatic MRP3/ABCC3 by Xenobiotics and Pathophysiological Conditions: Role in Drug Pharmacokinetics. Curr Med Chem 2019; 26:1185-1223. [PMID: 29473496 DOI: 10.2174/0929867325666180221142315] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Revised: 01/17/2018] [Accepted: 02/05/2018] [Indexed: 12/13/2022]
Abstract
Liver transporters play an important role in the pharmacokinetics and disposition of pharmaceuticals, environmental contaminants, and endogenous compounds. Among them, the family of ATP-Binding Cassette (ABC) transporters is the most important due to its role in the transport of endo- and xenobiotics. The ABCC sub-family is the largest one, consisting of 13 members that include the cystic fibrosis conductance regulator (CFTR/ABCC7); the sulfonylurea receptors (SUR1/ABCC8 and SUR2/ABCC9) and the multidrug resistanceassociated proteins (MRPs). The MRP-related proteins can collectively confer resistance to natural, synthetic drugs and their conjugated metabolites, including platinum-containing compounds, folate anti-metabolites, nucleoside and nucleotide analogs, among others. MRPs can be also catalogued into "long" (MRP1/ABCC1, -2/C2, -3/C3, -6/C6, and -7/C10) and "short" (MRP4/C4, -5/C5, -8/C11, -9/C12, and -10/C13) categories. While MRP2/ABCC2 is expressed in the canalicular pole of hepatocytes, all others are located in the basolateral membrane. In this review, we summarize information from studies examining the changes in expression and regulation of the basolateral hepatic transporter MPR3/ABCC3 by xenobiotics and during various pathophysiological conditions. We also focus, primarily, on the consequences of such changes in the pharmacokinetic, pharmacodynamic and/or toxicity of different drugs of clinical use transported by MRP3.
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Affiliation(s)
- Carolina I Ghanem
- Instituto de Investigaciones Farmacologicas (ININFA), Facultad de Farmacia y Bioquimica. CONICET. Universidad de Buenos Aires, Buenos Aires, Argentina.,Catedra de Fisiopatologia. Facultad de Farmacia y Bioquimica. Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Jose E Manautou
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, United States
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M Z, S M D, F E, M R F, M M, S M B T. Molecular Modelling and Evaluation of Hidden Information in ABCB11 Gene Mutations. J Biomed Phys Eng 2019; 9:303-316. [PMID: 31341876 PMCID: PMC6613151 DOI: 10.31661/jbpe.v9i3jun.680] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Accepted: 12/20/2016] [Indexed: 02/05/2023]
Abstract
BACKGROUND Cholestatic disorders are divided in the extra and intra-hepatic that created due to the severe liver diseases. ABCB11 encodes the bile salt export pump and this gene is mutated in several forms of intrahepatic cholestasis. So far, some molecular features of this gene was studies. OBJECTIVE Using a developed web server, we identified high number of rare codons in this gene, and four cases were related to BSEP-deficient patients which can be used for drug design. MATERIAL AND METHODS By in-silico modelling of ABCB11, some of rare codons in different locations of ATP8b1 gene were identified and evaluated. Using several web servers a number of mutations that converted non-rare codons to rare codon in these patients were identified. RESULTS Some of these rare Codons were located at special positions by mutation of which, the new side chains do not seem suitable for protein structure and function. Furthermore, this mutation changed the protein folding rate that may have a critical role in proper folding. Thus, primary change of these codons contributes to BSEP deficiency. CONCLUSION This work is a comprehensive analysis of rare codons of ABCB11 and assessment of a number of these rare codon in protein levels. Rare codons evaluation can enhance our understanding of ABCB11 structural protein of ABCB11, and help us to develop mutation-specific therapies in design of new drugs.
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Affiliation(s)
- Zarenezhad M
- MD, PhD, Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- MD, PhD, legal medicine research center, legal medicine organization, Tehran , iran
| | - Dehghani S M
- MD, Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ejtehadi F
- MD, Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Fattahi M R
- MD, Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mortazavi M
- PhD, Department of Biotechnology, Institute of Science and High Technology and Environmental Science, Graduate University of Advanced Technology, Kerman, Iran
| | - Tabei S M B
- MD, Genetic Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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Morita SY, Ikeda Y, Tsuji T, Terada T. Molecular Mechanisms for Protection of Hepatocytes against Bile Salt Cytotoxicity. Chem Pharm Bull (Tokyo) 2019; 67:333-340. [DOI: 10.1248/cpb.c18-01029] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- Shin-ya Morita
- Department of Pharmacy, Shiga University of Medical Science Hospital
| | - Yoshito Ikeda
- Department of Pharmacy, Shiga University of Medical Science Hospital
| | - Tokuji Tsuji
- Department of Pharmacy, Shiga University of Medical Science Hospital
| | - Tomohiro Terada
- Department of Pharmacy, Shiga University of Medical Science Hospital
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Chan R, Benet LZ. Measures of BSEP Inhibition In Vitro Are Not Useful Predictors of DILI. Toxicol Sci 2019; 162:499-508. [PMID: 29272540 DOI: 10.1093/toxsci/kfx284] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Inhibition of the bile salt export pump (BSEP) by a drug has been implicated as a risk factor for a drug's potential to cause drug-induced liver injury (DILI) and is thought to be an important mechanism leading to DILI. For a wide variety of drugs a correlation has been observed between the potency of in vitro BSEP inhibition and its propensity to cause DILI in humans. These findings were interpreted to suggest that BSEP inhibition could be an important mechanism to help explain how some drugs initiate DILI. Because the Biopharmaceutics Drug Disposition Classification System (BDDCS) can be useful in characterizing and predicting some important transporter effects in terms of drug-drug interactions, we evaluated the information provided by BDDCS in order to understand the inhibition propensity of BSEP. Here we analyze the relationship between a compound's ability to inhibit BSEP function and cause liver injury in humans using a compilation of published DILI datasets that have screened for BSEP inhibitors, other hepatic transporters and other mechanism-based toxicity key events. Our results demonstrate that there is little support for in vitro BSEP inhibition being universally DILI predictive. Rather we show that most potent BSEP inhibitors are BDDCS class 2 drugs, which we have demonstrated previously is the BDDCS class most likely to be DILI related. Since BDDCS class is not related to any proposed DILI mechanistic hypotheses, we maintain that if measures of BSEP inhibition alone or together with inhibition of other transporters cannot be differentiated from class 2 assignment, there is no support for in vitro BSEP inhibition being DILI predictive.
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Affiliation(s)
- Rosa Chan
- Department of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and Medicine, University of California, San Francisco, California
| | - Leslie Z Benet
- Department of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and Medicine, University of California, San Francisco, California
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Wang R, Sheps JA, Liu L, Han J, Chen PSK, Lamontagne J, Wilson PD, Welch I, Borchers CH, Ling V. Hydrophilic bile acids prevent liver damage caused by lack of biliary phospholipid in Mdr2-/- mice. J Lipid Res 2019; 60:85-97. [PMID: 30416103 PMCID: PMC6314265 DOI: 10.1194/jlr.m088070] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Revised: 11/04/2018] [Indexed: 12/15/2022] Open
Abstract
Bile acid imbalance causes progressive familial intrahepatic cholestasis type 2 (PFIC2) or type 3 (PFIC3), severe liver diseases associated with genetic defects in the biliary bile acid transporter bile salt export pump (BSEP; ABCB11) or phosphatidylcholine transporter multidrug resistance protein 3 (MDR3; ABCB4), respectively. Mdr2-/- mice (a PFIC3 model) develop progressive cholangitis, ductular proliferation, periportal fibrosis, and hepatocellular carcinoma (HCC) because the nonmicelle-bound bile acids in the bile of these mice are toxic. We asked whether the highly hydrophilic bile acids generated by Bsep-/- mice could protect Mdr2-/- mice from progressive liver damage. We generated double-KO (DKO: Bsep-/- and Mdr2-/- ) mice. Their bile acid composition resembles that of Bsep-/- mice, with increased hydrophilic muricholic acids, tetrahydroxylated bile acids (THBAs), and reduced hydrophobic cholic acid. These mice lack the liver pathology of their Mdr2-/- littermates. The livers of DKO mice have gene expression profiles very similar to Bsep-/- mice, with 4,410 of 6,134 gene expression changes associated with the Mdr2-/- mutation being suppressed. Feeding with THBAs partially alleviates liver damage in the Mdr2-/- mice. Hydrophilic changes to biliary bile acid composition, including introduction of THBA, can prevent the progressive liver pathology associated with the Mdr2-/- (PFIC3) mutation.
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Affiliation(s)
- Renxue Wang
- BC Cancer Research Centre, Vancouver, British Columbia, Canada
| | | | - Lin Liu
- BC Cancer Research Centre, Vancouver, British Columbia, Canada
| | - Jun Han
- University of Victoria-Genome BC Proteomics Centre University of Victoria, Victoria, British Columbia, Canada
| | - Patrick S K Chen
- Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada
| | - Jason Lamontagne
- Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada
| | - Peter D Wilson
- Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada
| | - Ian Welch
- Department of Pathology University of British Columbia, Vancouver, British Columbia, Canada
- Centre for Comparative Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Christoph H Borchers
- University of Victoria-Genome BC Proteomics Centre University of Victoria, Victoria, British Columbia, Canada
- Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia, Canada
- Proteomics Centre, Segal Cancer Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, Quebec, Canada
| | - Victor Ling
- BC Cancer Research Centre, Vancouver, British Columbia, Canada
- Department of Pathology University of British Columbia, Vancouver, British Columbia, Canada
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Abstract
Cholestasis is a condition that impairs bile flow, resulting in retention of bile fluid in the liver. It may cause significant morbidity and mortality due to pruritus, malnutrition, and complications from portal hypertension secondary to biliary cirrhosis. The zebrafish (Danio rerio) has emerged as a valuable model organism for studying cholestasis that complements with the in vitro systems and rodent models. Its main advantages include conserved mechanisms of liver development and bile formation, rapid external development, ease of monitoring hepatobiliary morphology and function in live larvae, and accessibility to genetic and chemical manipulations. In this chapter, we provide an overview of the existing zebrafish models of cholestatic liver diseases. We discuss the strengths and limitations of using zebrafish to study cholestasis. We also provide step-by-step descriptions of the methodologies for analyzing cholestatic phenotypes in zebrafish.
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Affiliation(s)
- Duc-Hung Pham
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Chunyue Yin
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. .,Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
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Cholestasis After Pediatric Liver Transplantation-Recurrence of a Progressive Familial Intrahepatic Cholestasis Phenotype as a Rare Differential Diagnosis: A Case Report. Transplant Proc 2018; 49:1628-1633. [PMID: 28838453 DOI: 10.1016/j.transproceed.2017.06.011] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Accepted: 06/16/2017] [Indexed: 12/17/2022]
Abstract
INTRODUCTION Nonobstructive cholestasis after pediatric liver transplantation is a common diagnostic and therapeutic dilemma. We describe a girl with neonatal cholestasis because of progressive familial intrahepatic cholestasis 2 (PFIC-2) and presence of a homozygous splice site mutation in the ABCB11 gene. Liver transplantation was performed because of end-stage liver disease at the age of 6. Cholestasis with normal gamma-glutamyl transferase (GGT) developed 8 years after liver transplantation. A liver biopsy showed canalicular cholestasis and giant cell hepatitis without evidence of rejection, mimicking PFIC-2. Immunofluorescence staining of normal human liver sections with patient's serum revealed reactivity toward a canalicular epitope, which could be identified as bile salt export pump (BSEP) using BSEP-yellow fluorescent protein (YFP) transfected cells. Our patient developed a recurrence of a PFIC-2 phenotype due to production of antibodies against BSEP (alloimmune BSEP disease [AIBD]). Intensification of immunosuppressive therapy as well as antibody treatment with plasmapheresis and Rituximab were initiated, leading to stabilization of the clinical condition and depletion of anti-BSEP antibodies in serum. However, after 1 year liver transplantation was necessary again because of end-stage liver insufficiency. Afterward, immunomodulatory treatment consisted of tacrolimus, mycophenolate mofetil, prednisone, immunoadsorption, and high-dose immunoglobulin therapy (1 g/kg/d). CONCLUSION Cholestasis after liver transplantation may indicate an AIBD with a PFIC-2 phenotype. Besides enhancement of immunosuppressive therapy, an antibody depletion with plasmapheresis, immunoadsorption, immunoglobulins, and B-cell depletion represents a therapeutic option.
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Macrophage-derived IL-1β/NF-κB signaling mediates parenteral nutrition-associated cholestasis. Nat Commun 2018; 9:1393. [PMID: 29643332 PMCID: PMC5895696 DOI: 10.1038/s41467-018-03764-1] [Citation(s) in RCA: 82] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2017] [Accepted: 03/12/2018] [Indexed: 12/15/2022] Open
Abstract
In infants intolerant of enteral feeding because of intestinal disease, parenteral nutrition may be associated with cholestasis, which can progress to end-stage liver disease. Here we show the function of hepatic macrophages and phytosterols in parenteral nutrition-associated cholestasis (PNAC) pathogenesis using a mouse model that recapitulates the human pathophysiology and combines intestinal injury with parenteral nutrition. We combine genetic, molecular, and pharmacological approaches to identify an essential function of hepatic macrophages and IL-1β in PNAC. Pharmacological antagonism of IL-1 signaling or genetic deficiency in CCR2, caspase-1 and caspase-11, or IL-1 receptor (which binds both IL-1α and IL-1β) prevents PNAC in mice. IL-1β increases hepatocyte NF-κB signaling, which interferes with farnesoid X receptor and liver X receptor bonding to respective promoters of canalicular bile and sterol transporter genes (Abcc2, Abcb11, and Abcg5/8), resulting in transcriptional suppression and subsequent cholestasis. Thus, hepatic macrophages, IL-1β, or NF-κB may be targets for restoring bile and sterol transport to treat PNAC.
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40
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Imagawa K, Hayashi H, Sabu Y, Tanikawa K, Fujishiro J, Kajikawa D, Wada H, Kudo T, Kage M, Kusuhara H, Sumazaki R. Clinical phenotype and molecular analysis of a homozygous ABCB11 mutation responsible for progressive infantile cholestasis. J Hum Genet 2018; 63:569-577. [PMID: 29507376 DOI: 10.1038/s10038-018-0431-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Revised: 02/02/2018] [Accepted: 02/07/2018] [Indexed: 01/26/2023]
Abstract
The bile salt export pump (BSEP) plays an important role in biliary secretion. Mutations in ABCB11, the gene encoding BSEP, induce progressive familial intrahepatic cholestasis type 2 (PFIC2), which presents with severe jaundice and liver dysfunction. A less severe phenotype, called benign recurrent intrahepatic cholestasis type 2, is also known. About 200 missense mutations in ABCB11 have been reported. However, the phenotype-genotype correlation has not been clarified. Furthermore, the frequencies of ABCB11 mutations differ between Asian and European populations. We report a patient with PFIC2 carrying a homozygous ABCB11 mutation c.386G>A (p.C129Y) that is most frequently reported in Japan. The pathogenicity of BSEPC129Y has not been investigated. In this study, we performed the molecular analysis of this ABCB11 mutation using cells expressing BSEPC129Y. We found that trafficking of BSEPC129Y to the plasma membrane was impaired and that the expression of BSEPC129Y on the cell surface was significantly lower than that in the control. The amount of bile acids transported via BSEPC129Y was also significantly lower than that via BSEPWT. The transport activity of BSEPC129Y may be conserved because the amount of membrane BSEPC129Y corresponded to the uptake of taurocholate into membrane vesicles. In conclusion, we demonstrated that c.386G>A (p.C129Y) in ABCB11 was a causative mutation correlating with the phenotype of patients with PFIC2, impairment of biliary excretion from hepatocytes, and the absence of canalicular BSEP expression in liver histological assessments. Mutational analysis in ABCB11 could facilitate the elucidation of the molecular mechanisms underlying the development of intrahepatic cholestasis.
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Affiliation(s)
- Kazuo Imagawa
- Department of Pediatrics, University of Tsukuba Hospital, Ibaraki, Japan. .,Department of Child Health, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan.
| | - Hisamitsu Hayashi
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
| | - Yusuke Sabu
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
| | - Ken Tanikawa
- Department of Diagnostic Pathology, Kurume University Hospital, Fukuoka, Japan
| | - Jun Fujishiro
- Department of Pediatric Surgery, Faculty of Medicine, The University of Tokyo, Tokyo, Japan
| | - Daigo Kajikawa
- Department of Pediatrics, University of Tsukuba Hospital, Ibaraki, Japan
| | - Hiroki Wada
- Department of Pediatrics, University of Tsukuba Hospital, Ibaraki, Japan
| | - Toyoichiro Kudo
- Department of Pediatrics, Mito Saiseikai General Hospital, Ibaraki, Japan
| | - Masayoshi Kage
- Department of Diagnostic Pathology, Kurume University Hospital, Fukuoka, Japan
| | - Hiroyuki Kusuhara
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
| | - Ryo Sumazaki
- Department of Child Health, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
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Stocchi L, Giardina E, Varriale L, Sechi A, Vagnini A, Parri G, Valentini M, Capalbo M. Can Tangier disease cause male infertility? A case report and an overview on genetic causes of male infertility and hormonal axis involved. Mol Genet Metab 2018; 123:43-49. [PMID: 29198592 DOI: 10.1016/j.ymgme.2017.11.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Revised: 11/24/2017] [Accepted: 11/24/2017] [Indexed: 11/18/2022]
Abstract
Tangier disease is an autosomal recessive disorder caused by mutations in the ABCA1 gene and characterized by the accumulation of cholesteryl ester in various tissues and a near absence of high-density lipoprotein. The subject in this investigation was a 36-year-old Italian man with Tangier disease. He and his wife had come to the In Vitro Fertilization Unit, Pesaro Hospital (Azienda Ospedaliera Ospedali Riuniti Marche Nord) seeking help regarding fertility issues. The man was diagnosed with severe oligoasthenoteratozoospermia. Testosterone is the sex hormone necessary for spermatogenesis and cholesterol is its precursor; hence, we hypothesized that the characteristic cholesterol deficiency in Tangier disease patients could compromise their fertility. The aim of the study was to therefore to determine if there is an association between Tangier disease and male infertility. After excluding viral, infectious, genetic and anatomical causes of the subject's oligoasthenoteratozoospermia, we performed a hormonal analysis to verify our hypothesis. The patient was found to be negative for frequent bacteria and viruses. The subject showed a normal male karyotype and tested negative for Yq microdeletions and Cystic Fibrosis Transmembrane Conductance Regulator gene mutations. A complete urological examination was performed, and primary hypogonadism was also excluded. Conversely, hormonal analyses showed that the subject had a high level of follicle stimulating hormone and luteinizing hormone, low total testosterone and a significant decline in inhibin B. We believe that the abnormally low cholesterol levels typically found in subjects with Tangier disease may result in a reduced testosterone production which in turn could affect the hormonal axis responsible for spermatogenesis leading to a defective maturation of spermatozoa.
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Affiliation(s)
- Laura Stocchi
- Pathophysiology of Reproduction, U.O.C., IVF Unit, Azienda Ospedaliera Ospedali Riuniti Marche Nord, Pesaro, Italy.
| | - Emiliano Giardina
- Laboratory of Genomic Medicine-UILDM, Fondazione Santa Lucia IRCCS, Univ. Tor Vergata; Rome, Italy.
| | - Luigia Varriale
- Department of Clinical Pathology, U.O.S.D. D.A.L.T., Azienda Ospedaliera Ospedali Riuniti Marche Nord, Pesaro, Italy.
| | - Annalisa Sechi
- Regional Center for Rare Diseases, Academic Hospital of Udine, Italy.
| | - Andrea Vagnini
- Department of Clinical Pathology, U.O.S.D. D.A.L.T., Azienda Ospedaliera Ospedali Riuniti Marche Nord, Pesaro, Italy.
| | - Gianni Parri
- Department of Urology, Azienda Ospedaliera Ospedali Riuniti Marche Nord, Pesaro, Italy.
| | - Massimo Valentini
- Department of Clinical Pathology, U.O.S.D. D.A.L.T., Azienda Ospedaliera Ospedali Riuniti Marche Nord, Pesaro, Italy.
| | - Maria Capalbo
- General Director of Azienda Ospedaliera Ospedali Riuniti Marche Nord, Pesaro, Italy.
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42
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Affiliation(s)
- Debra H Pan
- Division of Pediatric Gastroenterology and Nutrition, The Children's Hospital at Montefiore, Bronx, NY
| | - Yolanda Rivas
- Division of Pediatric Gastroenterology and Nutrition, The Children's Hospital at Montefiore, Bronx, NY
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43
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Vij M, Shanmugam NP, Reddy MS, Sankaranarayanan S, Rela M. Paediatric hepatocellular carcinoma in tight junction protein 2 (TJP2) deficiency. Virchows Arch 2017; 471:679-683. [PMID: 28733884 DOI: 10.1007/s00428-017-2204-1] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Revised: 06/30/2017] [Accepted: 07/12/2017] [Indexed: 12/12/2022]
Affiliation(s)
- Mukul Vij
- Department of Pathology, Institute of Liver Disease and Transplantation, Gleneagles Global Health City, Chennai, Tamil Nadu, 600100, India.
| | - Naresh P Shanmugam
- Institute of Liver Disease and Transplantation, Gleneagles Global Health City, Chennai, Tamil Nadu, 600100, India
| | - Mettu Srinivas Reddy
- Institute of Liver Disease and Transplantation, Gleneagles Global Health City, Chennai, Tamil Nadu, 600100, India
| | | | - Mohamed Rela
- Institute of Liver Disease and Transplantation, Gleneagles Global Health City, Chennai, Tamil Nadu, 600100, India
- National Foundation for Liver Research, Chennai, Tamil Nadu, India
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44
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Cariello M, Piccinin E, Garcia-Irigoyen O, Sabbà C, Moschetta A. Nuclear receptor FXR, bile acids and liver damage: Introducing the progressive familial intrahepatic cholestasis with FXR mutations. Biochim Biophys Acta Mol Basis Dis 2017; 1864:1308-1318. [PMID: 28965883 DOI: 10.1016/j.bbadis.2017.09.019] [Citation(s) in RCA: 65] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Revised: 09/15/2017] [Accepted: 09/17/2017] [Indexed: 02/07/2023]
Abstract
The nuclear receptor farnesoid X receptor (FXR) is the master regulator of bile acids (BAs) homeostasis since it transcriptionally drives modulation of BA synthesis, influx, efflux, and detoxification along the enterohepatic axis. Due to its crucial role, FXR alterations are involved in the progression of a plethora of BAs associated inflammatory disorders in the liver and in the gut. The involvement of the FXR pathway in cholestasis development and management has been elucidated so far with a direct role of FXR activating therapy in this condition. However, the recent identification of a new type of genetic progressive familial intrahepatic cholestasis (PFIC) linked to FXR mutations has strengthen also the bona fide beneficial effects of target therapies that by-pass FXR activation, directly promoting the action of its target, namely the enterokine FGF19, in the repression of hepatic BAs synthesis with reduction of total BA levels in the liver and serum, accomplishing one of the major goals in cholestasis. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni and Peter Jansen.
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Affiliation(s)
- Marica Cariello
- Department of Interdisciplinary Medicine, "Aldo Moro" University of Bari, 70124 Bari, Italy
| | - Elena Piccinin
- INBB, National Institute for Biostructures and Biosystems, 00136 Rome, Italy
| | - Oihane Garcia-Irigoyen
- Department of Interdisciplinary Medicine, "Aldo Moro" University of Bari, 70124 Bari, Italy
| | - Carlo Sabbà
- Department of Interdisciplinary Medicine, "Aldo Moro" University of Bari, 70124 Bari, Italy
| | - Antonio Moschetta
- Department of Interdisciplinary Medicine, "Aldo Moro" University of Bari, 70124 Bari, Italy; National Cancer Center, IRCCS Istituto Oncologico "Giovanni Paolo II", 70124 Bari, Italy.
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45
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Cheng Y, Chen S, Freeden C, Chen W, Zhang Y, Abraham P, Nelson DM, Humphreys WG, Gan J, Lai Y. Bile Salt Homeostasis in Normal and Bsep Gene Knockout Rats with Single and Repeated Doses of Troglitazone. J Pharmacol Exp Ther 2017; 362:385-394. [PMID: 28645914 DOI: 10.1124/jpet.117.242370] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2017] [Accepted: 06/22/2017] [Indexed: 12/17/2022] Open
Abstract
The interference of bile acid secretion through bile salt export pump (BSEP) inhibition is one of the mechanisms for troglitazone (TGZ)-induced hepatotoxicity. Here, we investigated the impact of single or repeated oral doses of TGZ (200 mg/kg/day, 7 days) on bile acid homoeostasis in wild-type (WT) and Bsep knockout (KO) rats. Following oral doses, plasma exposures of TGZ were not different between WT and KO rats, and were similar on day 1 and day 7. However, plasma exposures of the major metabolite, troglitazone sulfate (TS), in KO rats were 7.6- and 9.3-fold lower than in WT on day 1 and day 7, respectively, due to increased TS biliary excretion. With Bsep KO, the mRNA levels of multidrug resistance-associated protein 2 (Mrp2), Mrp3, Mrp4, Mdr1, breast cancer resistance protein (Bcrp), sodium taurocholate cotransporting polypeptide, small heterodimer partner, and Sult2A1 were significantly altered in KO rats. Following seven daily TGZ treatments, Cyp7A1 was significantly increased in both WT and KO rats. In the vehicle groups, plasma exposures of individual bile acids demonstrated variable changes in KO rats as compared with WT. WT rats dosed with TGZ showed an increase of many bile acid species in plasma on day 1, suggesting the inhibition of Bsep. Conversely, these changes returned to base levels on day 7. In KO rats, alterations of most bile acids were observed after seven doses of TGZ. Collectively, bile acid homeostasis in rats was regulated through bile acid synthesis and transport in response to Bsep deficiency and TGZ inhibition. Additionally, our study is the first to demonstrate that repeated TGZ doses can upregulate Cyp7A1 in rats.
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Affiliation(s)
- Yaofeng Cheng
- Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey
| | - Shenjue Chen
- Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey
| | - Chris Freeden
- Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey
| | - Weiqi Chen
- Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey
| | - Yueping Zhang
- Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey
| | - Pamela Abraham
- Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey
| | - David M Nelson
- Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey
| | - W Griffith Humphreys
- Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey
| | - Jinping Gan
- Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey
| | - Yurong Lai
- Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey
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46
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Lepist EI, Ray AS. Beyond drug-drug interactions: effects of transporter inhibition on endobiotics, nutrients and toxins. Expert Opin Drug Metab Toxicol 2017; 13:1075-1087. [PMID: 28847160 DOI: 10.1080/17425255.2017.1372425] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
INTRODUCTION Membrane transport proteins play a central role in regulating the disposition of endobiotics, dietary nutrients and environmental toxins. The inhibition of transporters by drugs has potential physiologic consequences. The full extent of the effect of drugs on the function of transporters is poorly understood because only a small subset of the hundreds of transporters expressed in humans - primarily those mediating the rate-determining step in the elimination of specific drugs - are assessed during clinical development. Areas covered: We provide a comprehensive overview of literature reports implicating the inhibition of transporters as the mechanism for off-target effects of drugs. Expert opinion: Transporter inhibition, the mechanism of action of many marketed drugs, appears to play an underappreciated role in a number of side effects including vitamin deficiency, edema, dyslipidemia, cholestasis and gout. Cell systems more broadly expressing transporter networks and methods like unbiased metabolomics should be incorporated into the screening paradigm to expand our understanding of the impact of drugs on the physiologic function of transporters and to allow for these effects to be taken into account in drug discovery and clinical practice.
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Affiliation(s)
- Eve-Irene Lepist
- a Departments of Drug Metabolism , Gilead Sciences, Inc ., Foster City , CA , USA
| | - Adrian S Ray
- b Clinical Research , Gilead Sciences, Inc ., Foster City , CA , USA
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47
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Zhang Y, Jackson JP, St Claire RL, Freeman K, Brouwer KR, Edwards JE. Obeticholic acid, a selective farnesoid X receptor agonist, regulates bile acid homeostasis in sandwich-cultured human hepatocytes. Pharmacol Res Perspect 2017; 5. [PMID: 28805978 PMCID: PMC5684861 DOI: 10.1002/prp2.329] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Accepted: 05/10/2017] [Indexed: 12/11/2022] Open
Abstract
Farnesoid X receptor (FXR) is a master regulator of bile acid homeostasis through transcriptional regulation of genes involved in bile acid synthesis and cellular membrane transport. Impairment of bile acid efflux due to cholangiopathies results in chronic cholestasis leading to abnormal elevation of intrahepatic and systemic bile acid levels. Obeticholic acid (OCA) is a potent and selective FXR agonist that is 100‐fold more potent than the endogenous ligand chenodeoxycholic acid (CDCA). The effects of OCA on genes involved in bile acid homeostasis were investigated using sandwich‐cultured human hepatocytes. Gene expression was determined by measuring mRNA levels. OCA dose‐dependently increased fibroblast growth factor‐19 (FGF‐19) and small heterodimer partner (SHP) which, in turn, suppress mRNA levels of cholesterol 7‐alpha‐hydroxylase (CYP7A1), the rate‐limiting enzyme for de novo synthesis of bile acids. Consistent with CYP7A1 suppression, total bile acid content was decreased by OCA (1 μmol/L) to 42.7 ± 20.5% relative to control. In addition to suppressing de novo bile acids synthesis, OCA significantly increased the mRNA levels of transporters involved in bile acid homeostasis. The bile salt excretory pump (BSEP), a canalicular efflux transporter, increased by 6.4 ± 0.8‐fold, and the basolateral efflux heterodimer transporters, organic solute transporter α (OSTα) and OSTβ increased by 6.4 ± 0.2‐fold and 42.9 ± 7.9‐fold, respectively. The upregulation of BSEP and OSTα and OSTβ, by OCA reduced the intracellular concentrations of d8‐TCA, a model bile acid, to 39.6 ± 8.9% relative to control. These data demonstrate that OCA does suppress bile acid synthesis and reduce hepatocellular bile acid levels, supporting the use of OCA to treat bile acid‐induced toxicity observed in cholestatic diseases.
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48
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Oya Y, Sugawara Y, Honda M, Yoshii D, Isono K, Hayashida S, Yamamoto H, Inomata Y. Living Donor Liver Transplantation for Progressive Familial Intrahepatic Cholestasis Type 1: Two Reported Cases. Transplant Proc 2017; 49:1123-1125. [PMID: 28583540 DOI: 10.1016/j.transproceed.2017.03.035] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
BACKGROUND Progressive familial intrahepatic cholestasis type 1 (PFIC1) is an inherited disease characterized by cholestatic features. We report two patients with PFIC1 who underwent liver retransplantation. CASE REPORT One patient was a 3-year-old female who underwent liver transplantation for PFIC1. She presented with severe diarrhea and fatty liver, and went into liver failure. She therefore underwent liver retransplantation and external biliary diversion 8 years after the initial liver transplantation. The explanted liver was histologically diagnosed with chronic rejection. Her intractable diarrhea stopped after the retransplantation. She was diagnosed with a fatty liver 8 months after the retransplantation and died 4 years after retransplantation due to bleeding from an ileostomy. The other patient was a 3-year-old male. This patient underwent liver retransplantation due to liver cirrhosis caused by steatohepatitis 9 years after the initial liver transplantation. The biliary tract was not diverted. He also experienced severe diarrhea after the retransplantation and requires home parenteral nutrition due to an eating disorder. CONCLUSIONS Liver transplantation is the only treatment to resolve life-threatening issues due to PFIC1, but requires further improvement as a therapeutic modality.
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Affiliation(s)
- Y Oya
- Department of Transplantation/Pediatric Surgery, Postgraduate School of Life Science, Kumamoto University, Kumamoto, Japan
| | - Y Sugawara
- Department of Transplantation/Pediatric Surgery, Postgraduate School of Life Science, Kumamoto University, Kumamoto, Japan.
| | - M Honda
- Department of Transplantation/Pediatric Surgery, Postgraduate School of Life Science, Kumamoto University, Kumamoto, Japan
| | - D Yoshii
- Department of Transplantation/Pediatric Surgery, Postgraduate School of Life Science, Kumamoto University, Kumamoto, Japan
| | - K Isono
- Department of Transplantation/Pediatric Surgery, Postgraduate School of Life Science, Kumamoto University, Kumamoto, Japan
| | - S Hayashida
- Department of Transplantation/Pediatric Surgery, Postgraduate School of Life Science, Kumamoto University, Kumamoto, Japan
| | - H Yamamoto
- Department of Transplantation/Pediatric Surgery, Postgraduate School of Life Science, Kumamoto University, Kumamoto, Japan
| | - Y Inomata
- Department of Transplantation/Pediatric Surgery, Postgraduate School of Life Science, Kumamoto University, Kumamoto, Japan
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49
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Jansen PLM, Ghallab A, Vartak N, Reif R, Schaap FG, Hampe J, Hengstler JG. The ascending pathophysiology of cholestatic liver disease. Hepatology 2017; 65:722-738. [PMID: 27981592 DOI: 10.1002/hep.28965] [Citation(s) in RCA: 225] [Impact Index Per Article: 28.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Revised: 10/26/2016] [Accepted: 11/17/2016] [Indexed: 02/06/2023]
Abstract
In this review we develop the argument that cholestatic liver diseases, particularly primary biliary cholangitis and primary sclerosing cholangitis (PSC), evolve over time with anatomically an ascending course of the disease process. The first and early lesions are in "downstream" bile ducts. This eventually leads to cholestasis, and this causes bile salt (BS)-mediated toxic injury of the "upstream" liver parenchyma. BS are toxic in high concentration. These concentrations are present in the canalicular network, bile ducts, and gallbladder. Leakage of bile from this network and ducts could be an important driver of toxicity. The liver has a great capacity to adapt to cholestasis, and this may contribute to a variable symptom-poor interval that is often observed. Current trials with drugs that target BS toxicity are effective in only about 50%-60% of primary biliary cholangitis patients, with no effective therapy in PSC. This motivated us to develop and propose a new view on the pathophysiology of primary biliary cholangitis and PSC in the hope that these new drugs can be used more effectively. These views may lead to better stratification of these diseases and to recommendations on a more "tailored" use of the new therapeutic agents that are currently tested in clinical trials. Apical sodium-dependent BS transporter inhibitors that reduce intestinal BS absorption lower the BS load and are best used in cholestatic patients. The effectiveness of BS synthesis-suppressing drugs, such as farnesoid X receptor agonists, is greatest when optimal adaptation is not yet established. By the time cytochrome P450 7A1 expression is reduced these drugs may be less effective. Anti-inflammatory agents are probably most effective in early disease, while drugs that antagonize BS toxicity, such as ursodeoxycholic acid and nor-ursodeoxycholic acid, may be effective at all disease stages. Endoscopic stenting in PSC should be reserved for situations of intercurrent cholestasis and cholangitis, not for cholestasis in end-stage disease. These are arguments to consider a step-wise pathophysiology for these diseases, with therapy adjusted to disease stage. An obstacle in such an approach is that disease stage-defining biomarkers are still lacking. This review is meant to serve as a call to prioritize the development of biomarkers that help to obtain a better stratification of these diseases. (Hepatology 2017;65:722-738).
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Affiliation(s)
- Peter L M Jansen
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.,Department of Surgery, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands.,Research Network of Liver Systems Medicine, Freiburg, Germany
| | - Ahmed Ghallab
- Research Network of Liver Systems Medicine, Freiburg, Germany.,Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany.,Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt
| | - Nachiket Vartak
- Research Network of Liver Systems Medicine, Freiburg, Germany.,Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany
| | - Raymond Reif
- Research Network of Liver Systems Medicine, Freiburg, Germany.,Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany
| | - Frank G Schaap
- Department of Surgery, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
| | - Jochen Hampe
- Research Network of Liver Systems Medicine, Freiburg, Germany.,Department of Medicine 1, Technical University Dresden, Dresden, Germany
| | - Jan G Hengstler
- Research Network of Liver Systems Medicine, Freiburg, Germany.,Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany
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50
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Burbank MG, Burban A, Sharanek A, Weaver RJ, Guguen-Guillouzo C, Guillouzo A. Early Alterations of Bile Canaliculi Dynamics and the Rho Kinase/Myosin Light Chain Kinase Pathway Are Characteristics of Drug-Induced Intrahepatic Cholestasis. Drug Metab Dispos 2016; 44:1780-1793. [PMID: 27538918 DOI: 10.1124/dmd.116.071373] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2016] [Accepted: 08/11/2016] [Indexed: 01/01/2023] Open
Abstract
Intrahepatic cholestasis represents 20%-40% of drug-induced injuries from which a large proportion remains unpredictable. We aimed to investigate mechanisms underlying drug-induced cholestasis and improve its early detection using human HepaRG cells and a set of 12 cholestatic drugs and six noncholestatic drugs. In this study, we analyzed bile canaliculi dynamics, Rho kinase (ROCK)/myosin light chain kinase (MLCK) pathway implication, efflux inhibition of taurocholate [a predominant bile salt export pump (BSEP) substrate], and expression of the major canalicular and basolateral bile acid transporters. We demonstrated that 12 cholestatic drugs classified on the basis of reported clinical findings caused disturbances of both bile canaliculi dynamics, characterized by either dilatation or constriction, and alteration of the ROCK/MLCK signaling pathway, whereas noncholestatic compounds, by contrast, had no effect. Cotreatment with ROCK inhibitor Y-27632 [4-(1-aminoethyl)-N-(4-pyridyl) cyclohexanecarboxamide dihydrochloride] and MLCK activator calmodulin reduced bile canaliculi constriction and dilatation, respectively, confirming the role of these pathways in drug-induced intrahepatic cholestasis. By contrast, inhibition of taurocholate efflux and/or human BSEP overexpressed in membrane vesicles was not observed with all cholestatic drugs; moreover, examples of noncholestatic compounds were reportedly found to inhibit BSEP. Transcripts levels of major bile acid transporters were determined after 24-hour treatment. BSEP, Na+-taurocholate cotransporting polypeptide, and organic anion transporting polypeptide B were downregulated with most cholestatic and some noncholestatic drugs, whereas deregulation of multidrug resistance-associated proteins was more variable, probably mainly reflecting secondary effects. Together, our results show that cholestatic drugs consistently cause an early alteration of bile canaliculi dynamics associated with modulation of ROCK/MLCK and these changes are more specific than efflux inhibition measurements alone as predictive nonclinical markers of drug-induced cholestasis.
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Affiliation(s)
- Matthew G Burbank
- INSERM UMR991, Foie, Métabolismes et Cancer, Rennes, France (M.G.B., A.B., A.S., C.G.-G., A.G.); Université Rennes 1, Rennes, France (M.G.B., A.B., A.S., C.G.-G., A.G.); Biologie Servier, Gidy, France (M.G.B.); Institut de Recherches Internationales Servier, Suresnes, France (R.J.W.); and Biopredic International, St. Grégoire, Rennes, France (C.G.-G.)
| | - Audrey Burban
- INSERM UMR991, Foie, Métabolismes et Cancer, Rennes, France (M.G.B., A.B., A.S., C.G.-G., A.G.); Université Rennes 1, Rennes, France (M.G.B., A.B., A.S., C.G.-G., A.G.); Biologie Servier, Gidy, France (M.G.B.); Institut de Recherches Internationales Servier, Suresnes, France (R.J.W.); and Biopredic International, St. Grégoire, Rennes, France (C.G.-G.)
| | - Ahmad Sharanek
- INSERM UMR991, Foie, Métabolismes et Cancer, Rennes, France (M.G.B., A.B., A.S., C.G.-G., A.G.); Université Rennes 1, Rennes, France (M.G.B., A.B., A.S., C.G.-G., A.G.); Biologie Servier, Gidy, France (M.G.B.); Institut de Recherches Internationales Servier, Suresnes, France (R.J.W.); and Biopredic International, St. Grégoire, Rennes, France (C.G.-G.)
| | - Richard J Weaver
- INSERM UMR991, Foie, Métabolismes et Cancer, Rennes, France (M.G.B., A.B., A.S., C.G.-G., A.G.); Université Rennes 1, Rennes, France (M.G.B., A.B., A.S., C.G.-G., A.G.); Biologie Servier, Gidy, France (M.G.B.); Institut de Recherches Internationales Servier, Suresnes, France (R.J.W.); and Biopredic International, St. Grégoire, Rennes, France (C.G.-G.)
| | - Christiane Guguen-Guillouzo
- INSERM UMR991, Foie, Métabolismes et Cancer, Rennes, France (M.G.B., A.B., A.S., C.G.-G., A.G.); Université Rennes 1, Rennes, France (M.G.B., A.B., A.S., C.G.-G., A.G.); Biologie Servier, Gidy, France (M.G.B.); Institut de Recherches Internationales Servier, Suresnes, France (R.J.W.); and Biopredic International, St. Grégoire, Rennes, France (C.G.-G.)
| | - André Guillouzo
- INSERM UMR991, Foie, Métabolismes et Cancer, Rennes, France (M.G.B., A.B., A.S., C.G.-G., A.G.); Université Rennes 1, Rennes, France (M.G.B., A.B., A.S., C.G.-G., A.G.); Biologie Servier, Gidy, France (M.G.B.); Institut de Recherches Internationales Servier, Suresnes, France (R.J.W.); and Biopredic International, St. Grégoire, Rennes, France (C.G.-G.)
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