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Song JQ, Zhou T, Luo Y, Liu Y. Internal biliary diversion using appendix during liver transplantation for progressive familial intrahepatic cholestasis type 1: A case report. World J Gastrointest Surg 2025; 17:101239. [DOI: 10.4240/wjgs.v17.i2.101239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Revised: 11/08/2024] [Accepted: 12/17/2024] [Indexed: 01/22/2025] Open
Abstract
BACKGROUND Progressive familial intrahepatic cholestasis type 1 (PFIC-1) is a genetic cholestatic disease causing end-stage liver disease, which needs liver transplantation (LT). Simultaneous biliary diversion (BD) was recommended to prevent allograft steatosis after transplantation, while increasing the risk of infection. Here, an attempt was made to perform BD using appendix to prevent bacterial translocation after LT.
CASE SUMMARY An 11-month-old boy diagnosed with PFIC-1 received ABO compatible living donor LT due to refractory jaundice and pruritus. His mother donated her left lateral segment with a graft-to-recipient weight ratio of 2.9%. Internal BD was constructed during LT using the appendix by connecting its proximal end with the intrahepatic biliary duct and the distal end with colon. Biliary leakage was suspected on the 5th day after transplantation and exploratory laparotomy indicated biliary leakage at the cutting surface of liver. The liver function returned to normal on the 9th day post-operation and maintained normal during the 15-month follow-up. Cholangiography at 10 months after transplantation confirmed the direct secretion of bile into colon. Computerized tomography scan (4 months and 10 months) and liver biopsy (10 months) indicated no steatosis in the allograft. No complaint of recurrent diarrhea, infection or growth retardation was reported during follow-up.
CONCLUSION Internal BD using appendix during LT is effective in preventing allograft steatosis and post-transplant infection in PFIC-1 recipients.
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Affiliation(s)
- Jia-Qi Song
- Department of Liver Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Tao Zhou
- Department of Liver Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Yi Luo
- Department of Liver Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Yuan Liu
- Department of Liver Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
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2
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Li JQ, Zhu YY, Xue MY, Chi H, Xie XB, Lu Y, Wang JS. Clinical features and long-term outcomes of patients with ZFYVE19 variants. Dig Liver Dis 2025; 57:S1590-8658(25)00195-1. [PMID: 39894731 DOI: 10.1016/j.dld.2025.01.183] [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: 09/03/2024] [Revised: 12/05/2024] [Accepted: 01/06/2025] [Indexed: 02/04/2025]
Abstract
BACKGROUND ZFYVE19-associated progressive familial intrahepatic cholestasis is a rare ciliopathy, with limited information on its natural history. AIMS Investigate long-term outcomes, especially after liver transplantation (LT), in ZFYVE19-deficient patients. METHODS Medical data of 13 Chinese individuals genetically diagnosed with ZFYVE19 deficiency, including 4 unreported patients, were reviewed. RESULTS All patients harbored biallelic null variants in ZFYVE19 and were alive at a median age of 13.2 years (range 1.1-39) with a median follow-up of 6.4 years (range 1-19.7). The first manifestation was neonatal cholestasis in 4 patients, isolated abnormal hepatobiliary-injury biomarkers in 3, and portal hypertension in 6. Eleven patients were administered ursodeoxycholic acid, with temporary normalization of hepatobiliary-injury biomarkers in 7. Six patients underwent LT (4 with living-related donors) at a median age of 3.5 years (range 0.6-7). After a median follow-up of 5.3 years (range 0.5-19) after LT, all 6 patients survived and were asymptomatic. Chronic renal disease or malignancy has not supervened. CONCLUSION ZFYVE19 deficiency caused by biallelic null variants primarily affects the liver without clinically significant involvement of other organs. ZFYVE19-related neonatal cholestasis can progress to liver failure necessitating LT in infancy. Ursodeoxycholic acid may improve hepatobiliary indices but may not avoid cirrhosis / LT. LT outcomes are generally good, even with parental grafts.
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Affiliation(s)
- Jia-Qi Li
- The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, Shanghai, 201102, China
| | - Yue-Yong Zhu
- Department of Liver Disease, The First Affiliated Hospital of Fujian Medical University, Fujian, 350000, China.
| | - Mei-Yan Xue
- Department of Liver Disease, The First Affiliated Hospital of Fujian Medical University, Fujian, 350000, China
| | - Hao Chi
- The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, Shanghai, 201102, China
| | - Xin-Bao Xie
- The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, Shanghai, 201102, China
| | - Yi Lu
- The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, Shanghai, 201102, China.
| | - Jian-She Wang
- The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, Shanghai, 201102, China.
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3
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Shin HW, Takatsu H. Substrates, regulation, cellular functions, and disease associations of P4-ATPases. Commun Biol 2025; 8:135. [PMID: 39875509 PMCID: PMC11775268 DOI: 10.1038/s42003-025-07549-3] [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: 09/04/2024] [Accepted: 01/14/2025] [Indexed: 01/30/2025] Open
Abstract
P4-ATPases, a subfamily of the P-type ATPase superfamily, play a crucial role in translocating membrane lipids from the exoplasmic/luminal leaflet to the cytoplasmic leaflet. This process generates and regulates transbilayer lipid asymmetry. These enzymes are conserved across all eukaryotes, and the human genome encodes 14 distinct P4-ATPases. Initially identified as aminophospholipid translocases, P4-ATPases have since been found to translocate other phospholipids, including phosphatidylcholine, phosphatidylinositol, and even glycosphingolipids. Recent advances in structural analysis have significantly improved our understanding of the lipid transport machinery associated with P4-ATPases, as documented in recent reviews. In this review, we highlight the emerging evidence related to substrate diversity, the regulation of cellular localization, enzymatic activities, and their impact on organism homeostasis and diseases.
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Affiliation(s)
- Hye-Won Shin
- Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan.
| | - Hiroyuki Takatsu
- Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan
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Hayes CM, Gallucci GM, Boyer JL, Assis DN, Ghonem NS. PPAR agonists for the treatment of cholestatic liver diseases: Over a decade of clinical progress. Hepatol Commun 2025; 9:e0612. [PMID: 39699308 PMCID: PMC11661771 DOI: 10.1097/hc9.0000000000000612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Accepted: 11/13/2024] [Indexed: 12/20/2024] Open
Abstract
Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are characterized by the destruction of the small bile ducts and the formation of multifocal biliary strictures, respectively, impairing bile flow. This leads to the hepatic accumulation of bile acids, causing liver injury and the risk of progression to cirrhosis and liver failure. First-line therapy for PBC is ursodeoxycholic acid, although up to 40% of treated individuals are incomplete responders, and there is no effective therapy for PSC, highlighting the need for better therapeutic options in these diseases. In addition, pruritus is a common symptom of cholestasis that has severe consequences for quality of life and is often undertreated or untreated. Nuclear receptors are pharmacological targets to treat cholestasis due to their multifactorial regulation of hepatic enzymatic pathways, particularly in bile acid metabolism. The peroxisome proliferator-activated receptor (PPAR) is of significant clinical interest due to its role in regulating bile acid synthesis and detoxification pathways. PPAR agonism by fibrates has traditionally been explored due to PPARα's expression in the liver; however, recent interest has expanded to focus on newer PPAR agonists that activate other PPAR isoforms, for example, δ, γ, alone or in combination. Several PPAR agonists have been investigated as second-line therapy for people living with PBC, including the recent accelerated United States Food and Drug Administration approval of elafibranor and seladelpar. This review evaluates available data on the efficacy and safety of the five PPAR agonists investigated for the treatment of cholestasis and associated pruritus in PBC and PSC, namely fenofibrate, bezafibrate, saroglitazar, elafibranor, and seladelpar.
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Affiliation(s)
- Colleen M. Hayes
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, USA
| | - Gina M. Gallucci
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, USA
| | - James L. Boyer
- Section of Digestive Diseases and Yale Liver Center, Yale School of Medicine, New Haven, Connecticut, USA
| | - David N. Assis
- Section of Digestive Diseases and Yale Liver Center, Yale School of Medicine, New Haven, Connecticut, USA
| | - Nisanne S. Ghonem
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, USA
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5
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Percheron A, Guerry P, Fabre A. PytheasDB: An open-access graphical database of clinical data on rare pediatric digestive diseases. Intractable Rare Dis Res 2024; 13:255-258. [PMID: 39628627 PMCID: PMC11609038 DOI: 10.5582/irdr.2024.01043] [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: 08/20/2024] [Revised: 09/23/2024] [Accepted: 10/01/2024] [Indexed: 12/06/2024] Open
Abstract
Advances in genetic testing over the past decades are driving a continuing increase in the diagnosis and reporting of rare genetic diseases, but no tool has yet been developed to aggregate published molecular and phenotypic data, a task that is nevertheless essential to optimize patient care. In this article, we present PytheasDB, an online database of published clinical data from patients with rare digestive diseases. At the time of writing (August 2024), the database contains data from 833 patients with progressive familial intrahepatic cholestasis or trichohepatoenteric syndrome, collected from 172 articles. Users can compare the phenotypic profiles, sex ratios, survival curves, ages at first symptoms, and consanguinity rates of the included diseases. PytheasDB is the first ever online resource providing access to aggregated clinical data from case reports of rare digestive diseases in the literature. The database is currently being expanded to cover ultra-rare pediatric digestive diseases with regular updates to optimize the study and treatment of these diseases.
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Affiliation(s)
- Alice Percheron
- APHM, Timone Children's Hospital, Department of Multidisciplinary Pediatrics, Marseille, France
| | | | - Alexandre Fabre
- APHM, Timone Children's Hospital, Department of Multidisciplinary Pediatrics, Marseille, France
- Aix Marseille University, INSERM, MMG, Marseille, France
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6
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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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7
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Koelink PJ, Gómez-Mellado VE, Duijst S, van Roest M, Meisner S, Ho-Mok KS, Frank S, Appelman BS, Bloemendaal LT, Vogel GF, van de Graaf SFJ, Bosma PJ, Oude Elferink RPJ, Wildenberg ME, Paulusma CC. The Phospholipid Flippase ATP8B1 is Involved in the Pathogenesis of Ulcerative Colitis via Establishment of Intestinal Barrier Function. J Crohns Colitis 2024; 18:1134-1146. [PMID: 38366839 PMCID: PMC11302967 DOI: 10.1093/ecco-jcc/jjae024] [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: 11/07/2023] [Revised: 01/30/2024] [Accepted: 02/15/2024] [Indexed: 02/18/2024]
Abstract
AIMS Patients with mutations in ATP8B1 develop progressive familial intrahepatic cholestasis type 1 [PFIC1], a severe liver disease that requires life-saving liver transplantation. PFIC1 patients also present with gastrointestinal problems, including intestinal inflammation and diarrhoea, which are aggravated after liver transplantation. Here we investigate the intestinal function of ATP8B1 in relation to inflammatory bowel diseases. METHODS ATP8B1 expression was investigated in intestinal samples of patients with Crohn's disease [CD] or ulcerative colitis [UC] as well as in murine models of intestinal inflammation. Colitis was induced in ATP8B1-deficient mice with dextran sodium sulphate [DSS] and intestinal permeability was investigated. Epithelial barrier function was assessed in ATP8B1 knockdown Caco2-BBE cells. Co-immunoprecipitation experiments were performed in Caco2-BBE cells overexpressing ATP8B1-eGFP. Expression and localization of ATP8B1 and tight junction proteins were investigated in cells and in biopsies of UC and PFIC1 patients. RESULTS ATP8B1 expression was decreased in UC and DSS-treated mice, and was associated with a decreased tight junctional pathway transcriptional programme. ATP8B1-deficient mice were extremely sensitive to DSS-induced colitis, as evidenced by increased intestinal barrier leakage. ATP8B1 knockdown cells showed delayed barrier establishment that affected Claudin-4 [CLDN4] levels and localization. CLDN4 immunohistochemistry showed a tight junctional staining in control tissue, whereas in UC and intestinal PFIC1 samples, CLDN4 was not properly localized. CONCLUSION ATP8B1 is important in the establishment of the intestinal barrier. Downregulation of ATP8B1 levels in UC, and subsequent altered localization of tight junctional proteins, including CLDN4, might therefore be an important mechanism in UC pathophysiology.
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Affiliation(s)
- Pim J Koelink
- Amsterdam University Medical Centers, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Amsterdam, The Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands
| | - Valentina E Gómez-Mellado
- Amsterdam University Medical Centers, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Amsterdam, The Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands
| | - Suzanne Duijst
- Amsterdam University Medical Centers, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Amsterdam, The Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands
| | - Manon van Roest
- Amsterdam University Medical Centers, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Amsterdam, The Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands
| | - Sander Meisner
- Amsterdam University Medical Centers, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Amsterdam, The Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands
| | - Kam S Ho-Mok
- Amsterdam University Medical Centers, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Amsterdam, The Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands
| | - Sabrina Frank
- Amsterdam University Medical Centers, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Amsterdam, The Netherlands
| | - Babette S Appelman
- Amsterdam University Medical Centers, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Amsterdam, The Netherlands
| | - Lysbeth ten Bloemendaal
- Amsterdam University Medical Centers, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Amsterdam, The Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands
| | - Georg F Vogel
- Department of Paediatrics I, Medical University of Innsbruck, 6020 Innsbruck, Austria
- Institute of Cell Biology, Biocenter, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Stan F J van de Graaf
- Amsterdam University Medical Centers, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Amsterdam, The Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
| | - Piter J Bosma
- Amsterdam University Medical Centers, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Amsterdam, The Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
| | - Ronald P J Oude Elferink
- Amsterdam University Medical Centers, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Amsterdam, The Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
| | - Manon E Wildenberg
- Amsterdam University Medical Centers, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Amsterdam, The Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
| | - Coen C Paulusma
- Amsterdam University Medical Centers, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Amsterdam, The Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands
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Guerrero L, Carmona-Rodríguez L, Santos FM, Ciordia S, Stark L, Hierro L, Pérez-Montero P, Vicent D, Corrales FJ. Molecular basis of progressive familial intrahepatic cholestasis 3. A proteomics study. Biofactors 2024; 50:794-809. [PMID: 38284625 DOI: 10.1002/biof.2041] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 12/18/2023] [Indexed: 01/30/2024]
Abstract
Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a severe rare liver disease that affects between 1/50,000 and 1/100,000 children. In physiological conditions, bile is produced by the liver and stored in the gallbladder, and then it flows to the small intestine to play its role in fat digestion. To prevent tissue damage, bile acids (BAs) are kept in phospholipid micelles. Mutations in phosphatidyl choline transporter ABCB4 (MDR3) lead to intrahepatic accumulation of free BAs that result in liver damage. PFIC3 onset usually occurs at early ages, progresses rapidly, and the prognosis is poor. Currently, besides the palliative use of ursodeoxycholate, the only available treatment for this disease is liver transplantation, which is really challenging for short-aged patients. To gain insight into the pathogenesis of PFIC3 we have performed an integrated proteomics and phosphoproteomics study in human liver samples to then validate the emerging functional hypotheses in a PFIC3 murine model. We identified 6246 protein groups, 324 proteins among them showing differential expression between control and PFIC3. The phosphoproteomic analysis allowed the identification of 5090 phosphopeptides, from which 215 corresponding to 157 protein groups, were differentially phosphorylated in PFIC3, including MDR3. Regulation of essential cellular processes and structures, such as inflammation, metabolic reprogramming, cytoskeleton and extracellular matrix remodeling, and cell proliferation, were identified as the main drivers of the disease. Our results provide a strong molecular background that significantly contributes to a better understanding of PFIC3 and provides new concepts that might prove useful in the clinical management of patients.
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Affiliation(s)
- Laura Guerrero
- Functional Proteomics Labortory, Centro Nacional de Biotecnología (CNB-CSIC), Madrid, Spain
| | | | - Fátima Milhano Santos
- Functional Proteomics Labortory, Centro Nacional de Biotecnología (CNB-CSIC), Madrid, Spain
| | - Sergio Ciordia
- Functional Proteomics Labortory, Centro Nacional de Biotecnología (CNB-CSIC), Madrid, Spain
| | - Luiz Stark
- IdiPAZ, Instituto de Investigación Sanitaria [Health Research Institute] of Hospital Universitario La Paz, Madrid, Spain
| | - Loreto Hierro
- IdiPAZ, Instituto de Investigación Sanitaria [Health Research Institute] of Hospital Universitario La Paz, Madrid, Spain
| | - Pablo Pérez-Montero
- Servicio de Anatomía Patológica, Hospital Universitario La Paz, Madrid, Spain
| | - David Vicent
- IdiPAZ, Instituto de Investigación Sanitaria [Health Research Institute] of Hospital Universitario La Paz, Madrid, Spain
| | - Fernando J Corrales
- Functional Proteomics Labortory, Centro Nacional de Biotecnología (CNB-CSIC), Madrid, Spain
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9
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Matsell E, Andersen JP, Molday RS. Functional and in silico analysis of ATP8A2 and other P4-ATPase variants associated with human genetic diseases. Dis Model Mech 2024; 17:dmm050546. [PMID: 38436085 PMCID: PMC11073571 DOI: 10.1242/dmm.050546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 02/21/2024] [Indexed: 03/05/2024] Open
Abstract
P4-ATPases flip lipids from the exoplasmic to cytoplasmic leaflet of cell membranes, a property crucial for many biological processes. Mutations in P4-ATPases are associated with severe inherited and complex human disorders. We determined the expression, localization and ATPase activity of four variants of ATP8A2, the P4-ATPase associated with the neurodevelopmental disorder known as cerebellar ataxia, impaired intellectual development and disequilibrium syndrome 4 (CAMRQ4). Two variants, G447R and A772P, harboring mutations in catalytic domains, expressed at low levels and mislocalized in cells. In contrast, the E459Q variant in a flexible loop displayed wild-type expression levels, Golgi-endosome localization and ATPase activity. The R1147W variant expressed at 50% of wild-type levels but showed normal localization and activity. These results indicate that the G447R and A772P mutations cause CAMRQ4 through protein misfolding. The E459Q mutation is unlikely to be causative, whereas the R1147W may display a milder disease phenotype. Using various programs that predict protein stability, we show that there is a good correlation between the experimental expression of the variants and in silico stability assessments, suggesting that such analysis is useful in identifying protein misfolding disease-associated variants.
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Affiliation(s)
- Eli Matsell
- Department of Biochemistry & Molecular Biology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada
| | | | - Robert S. Molday
- Department of Biochemistry & Molecular Biology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada
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10
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Duan HD, Li H. Consensus, controversies, and conundrums of P4-ATPases: The emerging face of eukaryotic lipid flippases. J Biol Chem 2024; 300:107387. [PMID: 38763336 PMCID: PMC11225554 DOI: 10.1016/j.jbc.2024.107387] [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: 03/26/2024] [Revised: 05/04/2024] [Accepted: 05/07/2024] [Indexed: 05/21/2024] Open
Abstract
The cryo-EM resolution revolution has heralded a new era in our understanding of eukaryotic lipid flippases with a rapidly growing number of high-resolution structures. Flippases belong to the P4 family of ATPases (type IV P-type ATPases) that largely follow the reaction cycle proposed for the more extensively studied cation-transporting P-type ATPases. However, unlike the canonical P-type ATPases, no flippase cargos are transported in the phosphorylation half-reaction. Instead of being released into the intracellular or extracellular milieu, lipid cargos are transported to their destination at the inner leaflet of the membrane. Recent flippase structures have revealed multiple conformational states during the lipid transport cycle. Nonetheless, critical conformational states capturing the lipid cargo "in transit" are still missing. In this review, we highlight the amazing structural advances of these lipid transporters, discuss various perspectives on catalytic and regulatory mechanisms in the literature, and shed light on future directions in further deciphering the detailed molecular mechanisms of lipid flipping.
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Affiliation(s)
- H Diessel Duan
- Department of Structural Biology, Van Andel Institute, Grand Rapids, Michigan, USA.
| | - Huilin Li
- Department of Structural Biology, Van Andel Institute, Grand Rapids, Michigan, USA.
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11
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Nittono H, Suzuki M, Suzuki H, Sugimoto S, Mori J, Sakamoto R, Takaki Y, Hayashi H, Takei H, Kimura A. Navigating cholestasis: identifying inborn errors of bile acid metabolism for precision diagnosis. Front Pediatr 2024; 12:1385970. [PMID: 38646510 PMCID: PMC11026588 DOI: 10.3389/fped.2024.1385970] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Accepted: 03/25/2024] [Indexed: 04/23/2024] Open
Abstract
Inborn errors of bile acid metabolism (IEBAM) cause cholestasis during the neonatal period, and 8 types of IEBAM have been reported to date. IEBAM accounts for approximately 2% of cases of cholestasis of unknown cause. As only 10 patients have been identified in Japan, IEBAM presents diagnostic challenges due to the similarity of clinical symptoms with biliary atresia, thus necessitating precise differentiation to avoid unnecessary invasive procedures. Laboratory tests in IEBAM are characterized by normal γ-glutamyltransferase (GGT) and serum total bile acid (STBA) levels despite the presence of cholestasis; therefore, measuring STBA and GGT is essential to distinguishing biliary atresia from IEBAM. With suspected IEBAM, liquid chromatography-mass spectrometry (LC/MS) analysis of urinary bile acids is needed to optimize diagnostic and therapeutic efficacy and avoid open cholangiography and initiate treatment for primary bile acids such as cholic acid or chenodeoxycholic acid. This prospective report aims to increase awareness of IEBAM by highlighting the characteristics of general blood test and bile acid profiles from LC/MS analyses of blood, urine, and stool samples.
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Affiliation(s)
- Hiroshi Nittono
- Division of Analysis Technology, Junshin Clinic Bile Acid Institute, Tokyo, Japan
| | - Mitsuyoshi Suzuki
- Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Hiromi Suzuki
- Division of Analysis Technology, Junshin Clinic Bile Acid Institute, Tokyo, Japan
- Department of Legal Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Satoru Sugimoto
- Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Jun Mori
- Division of Pediatric Endocrinology and Metabolism, Children’s Medical Center, Osaka City General Hospital, Osaka, Japan
| | - Rieko Sakamoto
- Department of Pediatrics and Pediatric Surgery, Juzen Hospital, Kumamoto, Japan
| | - Yugo Takaki
- Department of Pediatric Gastroenterology and Hepatology, Japanese Red Cross Kumamoto Hospital, Kumamoto, Japan
| | - Hisamitsu Hayashi
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo, Japan
| | - Hajime Takei
- Division of Analysis Technology, Junshin Clinic Bile Acid Institute, Tokyo, Japan
| | - Akihiko Kimura
- Department of Pediatrics, Kumamoto-Ashikita Medical Center for the Severity Disabled, Kumamoto, Japan
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12
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Norris AC, Mansueto AJ, Jimenez M, Yazlovitskaya EM, Jain BK, Graham TR. Flipping the script: Advances in understanding how and why P4-ATPases flip lipid across membranes. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2024; 1871:119700. [PMID: 38382846 DOI: 10.1016/j.bbamcr.2024.119700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 11/15/2023] [Accepted: 02/16/2024] [Indexed: 02/23/2024]
Abstract
Type IV P-type ATPases (P4-ATPases) are a family of transmembrane enzymes that translocate lipid substrates from the outer to the inner leaflet of biological membranes and thus create an asymmetrical distribution of lipids within membranes. On the cellular level, this asymmetry is essential for maintaining the integrity and functionality of biological membranes, creating platforms for signaling events and facilitating vesicular trafficking. On the organismal level, this asymmetry has been shown to be important in maintaining blood homeostasis, liver metabolism, neural development, and the immune response. Indeed, dysregulation of P4-ATPases has been linked to several diseases; including anemia, cholestasis, neurological disease, and several cancers. This review will discuss the evolutionary transition of P4-ATPases from cation pumps to lipid flippases, the new lipid substrates that have been discovered, the significant advances that have been achieved in recent years regarding the structural mechanisms underlying the recognition and flipping of specific lipids across biological membranes, and the consequences of P4-ATPase dysfunction on cellular and physiological functions. Additionally, we emphasize the requirement for additional research to comprehensively understand the involvement of flippases in cellular physiology and disease and to explore their potential as targets for therapeutics in treating a variety of illnesses. The discussion in this review will primarily focus on the budding yeast, C. elegans, and mammalian P4-ATPases.
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Affiliation(s)
- Adriana C Norris
- Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA
| | | | - Mariana Jimenez
- Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA
| | | | - Bhawik K Jain
- Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA
| | - Todd R Graham
- Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA.
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13
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Kita N, Hamamoto A, Gowda SGB, Takatsu H, Nakayama K, Arita M, Hui SP, Shin HW. Glucosylceramide flippases contribute to cellular glucosylceramide homeostasis. J Lipid Res 2024; 65:100508. [PMID: 38280458 PMCID: PMC10910339 DOI: 10.1016/j.jlr.2024.100508] [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] [Revised: 01/18/2024] [Accepted: 01/19/2024] [Indexed: 01/29/2024] Open
Abstract
Lipid transport is an essential cellular process with importance to human health, disease development, and therapeutic strategies. Type IV P-type ATPases (P4-ATPases) have been identified as membrane lipid flippases by utilizing nitrobenzoxadiazole (NBD)-labeled lipids as substrates. Among the 14 human type IV P-type ATPases, ATP10D was shown to flip NBD-glucosylceramide (GlcCer) across the plasma membrane. Here, we found that conversion of incorporated GlcCer (d18:1/12:0) to other sphingolipids is accelerated in cells exogenously expressing ATP10D but not its ATPase-deficient mutant. These findings suggest that 1) ATP10D flips unmodified GlcCer as well as NBD-GlcCer at the plasma membrane and 2) ATP10D can translocate extracellular GlcCer, which is subsequently converted to other metabolites. Notably, exogenous expression of ATP10D led to the reduction in cellular hexosylceramide levels. Moreover, the expression of GlcCer flippases, including ATP10D, also reduced cellular hexosylceramide levels in fibroblasts derived from patients with Gaucher disease, which is a lysosomal storage disorder with excess GlcCer accumulation. Our study highlights the contribution of ATP10D to the regulation of cellular GlcCer levels and maintaining lipid homeostasis.
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Affiliation(s)
- Natsuki Kita
- Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
| | - Asuka Hamamoto
- Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
| | - Siddabasave Gowda B Gowda
- Faculty of Health Sciences, Hokkaido University, Sapporo, Japan; Graduate School of Global Food Resources, Hokkaido University, Sapporo, Japan
| | - Hiroyuki Takatsu
- Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
| | - Kazuhisa Nakayama
- Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
| | - Makoto Arita
- Laboratory for Metabolomics, RIKEN Center of Integrative Medical Sciences, Yokohama, Japan
| | - Shu-Ping Hui
- Faculty of Health Sciences, Hokkaido University, Sapporo, Japan
| | - Hye-Won Shin
- Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
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14
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Wouters R, Beletchi I, Van den Haute C, Baekelandt V, Martin S, Eggermont J, Vangheluwe P. The lipid flippase ATP10B enables cellular lipid uptake under stress conditions. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2024; 1871:119652. [PMID: 38086447 DOI: 10.1016/j.bbamcr.2023.119652] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 10/27/2023] [Accepted: 12/04/2023] [Indexed: 12/23/2023]
Abstract
Pathogenic ATP10B variants have been described in patients with Parkinson's disease and dementia with Lewy body disease, and we previously established ATP10B as a late endo-/lysosomal lipid flippase transporting both phosphatidylcholine (PC) and glucosylceramide (GluCer) from the lysosomal exoplasmic to cytoplasmic membrane leaflet. Since several other lipid flippases regulate cellular lipid uptake, we here examined whether also ATP10B impacts cellular lipid uptake. Transient co-expression of ATP10B with its obligatory subunit CDC50A stimulated the uptake of fluorescently (NBD-) labeled PC in HeLa cells. This uptake is dependent on the transport function of ATP10B, is impaired by disease-associated variants and appears specific for NBD-PC. Uptake of non-ATP10B substrates, such as NBD-sphingomyelin or NBD-phosphatidylethanolamine is not increased. Remarkably, in stable cell lines co-expressing ATP10B/CDC50A we only observed increased NBD-PC uptake following treatment with rotenone, a mitochondrial complex I inhibitor that induces transport-dependent ATP10B phenotypes. Conversely, Im95m and WM-115 cells with endogenous ATP10B expression, present a decreased NBD-PC uptake following ATP10B knockdown, an effect that is exacerbated under rotenone stress. Our data show that the endo-/lysosomal lipid flippase ATP10B contributes to cellular PC uptake under specific cell stress conditions.
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Affiliation(s)
- Rosanne Wouters
- Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, KU Leuven, B-3000 Leuven, Belgium; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA
| | - Igor Beletchi
- Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, KU Leuven, B-3000 Leuven, Belgium
| | - Chris Van den Haute
- Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA; Leuven Viral Vector Core, KU Leuven, B-3000 Leuven, Belgium; Research Group for Neurobiology and Gene Therapy, Department of Neurosciences, KU Leuven, B-3000 Leuven, Belgium
| | - Veerle Baekelandt
- Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA; Research Group for Neurobiology and Gene Therapy, Department of Neurosciences, KU Leuven, B-3000 Leuven, Belgium
| | - Shaun Martin
- Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, KU Leuven, B-3000 Leuven, Belgium
| | - Jan Eggermont
- Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, KU Leuven, B-3000 Leuven, Belgium
| | - Peter Vangheluwe
- Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, KU Leuven, B-3000 Leuven, Belgium; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA.
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15
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Jeyaraj R, Maher ER, Kelly D. Paediatric research sets new standards for therapy in paediatric and adult cholestasis. THE LANCET. CHILD & ADOLESCENT HEALTH 2024; 8:75-84. [PMID: 38006895 DOI: 10.1016/s2352-4642(23)00259-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 09/18/2023] [Accepted: 09/22/2023] [Indexed: 11/27/2023]
Abstract
Children with Alagille syndrome and progressive familial intrahepatic cholestasis (PFIC) experience debilitating pruritus, for which there have been few effective treatment options. In the past 2 years, the ileal bile acid transporter (IBAT) inhibitors maralixibat and odevixibat have been approved for the management of cholestatic pruritus in these individuals, representing an important step forward in improving their quality of life. Emerging data suggest these drugs might also improve event-free survival, therefore potentially altering the typical disease course currently seen in these disorders. This Review will discuss how genetic advances have clarified the molecular basis of cholestatic disorders, facilitating the development of new therapeutic options that have only been evaluated in children. We focus specifically on the newly licensed IBAT inhibitors for patients with Alagille syndrome and PFIC and explore the next steps for these drugs in relation to other paediatric and adult cholestatic disorders, recognising that they have the potential to benefit a wider group of patients with gastrointestinal and liver disease.
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Affiliation(s)
- Rebecca Jeyaraj
- University College London Great Ormond Street Institute of Child Health, London, UK
| | - Eamonn R Maher
- Department of Medical Genetics, University of Cambridge, Cambridge, UK
| | - Deirdre Kelly
- The Liver Unit, Birmingham Women's and Children's Hospital, Birmingham, UK; University of Birmingham, Birmingham, UK.
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16
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Mogensen LS, Mikkelsen SA, Tadini-Buoninsegni F, Holm R, Matsell E, Vilsen B, Molday RS, Andersen JP. On the track of the lipid transport pathway of the phospholipid flippase ATP8A2 - Mutation analysis of residues of the transmembrane segments M1, M2, M3 and M4. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2024; 1871:119570. [PMID: 37678495 DOI: 10.1016/j.bbamcr.2023.119570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Accepted: 08/24/2023] [Indexed: 09/09/2023]
Abstract
P4-ATPases, also known as flippases, translocate specific lipids from the exoplasmic leaflet to the cytoplasmic leaflet of biological membranes, thereby generating an asymmetric lipid distribution essential for numerous cellular functions. A debated issue is which pathway within the protein the lipid substrate follows during the translocation. Here we present a comprehensive mutational screening of all amino acid residues in the transmembrane segments M1, M2, M3, and M4 of the flippase ATP8A2, thus allowing the functionally important residues in these transmembrane segments to be highlighted on a background of less important residues. Kinetic analysis of ATPase activity of 130 new ATP8A2 mutants, providing Vmax values as well as apparent affinities of the mutants for the lipid substrate, support a translocation pathway between M2 and M4 ("M2-M4 path"), extending from the entry site, where the lipid substrate binds from the exoplasmic leaflet, to a putative exit site at the cytoplasmic surface, formed by the divergence of M2 and M4. The effects of mutations in the M2-M4 path on the function of the entry site, including loss of lipid specificity in some mutants, suggest that the M2-M4 path and the entry site are conformationally coupled. Many of the residues of the M2-M4 path possess side chains with a potential for interacting with each other in a zipper-like mode, as well as with the head group of the lipid substrate, by ionic/hydrogen bonds. Thus, the translocation of the lipid substrate toward the cytoplasmic bilayer leaflet is comparable to unzipping a zipper of salt bridges/hydrogen bonds.
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Affiliation(s)
| | | | | | - Rikke Holm
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Eli Matsell
- Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Bente Vilsen
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Robert S Molday
- Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada; Department of Ophthalmology and Visual Sciences, Centre for Macular Research, University of British Columbia, Vancouver, British Columbia, Canada
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17
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Quaglia A, Roberts EA, Torbenson M. Developmental and Inherited Liver Disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:122-294. [DOI: 10.1016/b978-0-7020-8228-3.00003-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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18
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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] [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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19
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Dieudonné T, Kümmerer F, Laursen MJ, Stock C, Flygaard RK, Khalid S, Lenoir G, Lyons JA, Lindorff-Larsen K, Nissen P. Activation and substrate specificity of the human P4-ATPase ATP8B1. Nat Commun 2023; 14:7492. [PMID: 37980352 PMCID: PMC10657443 DOI: 10.1038/s41467-023-42828-9] [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: 04/12/2023] [Accepted: 10/23/2023] [Indexed: 11/20/2023] Open
Abstract
Asymmetric distribution of phospholipids in eukaryotic membranes is essential for cell integrity, signaling pathways, and vesicular trafficking. P4-ATPases, also known as flippases, participate in creating and maintaining this asymmetry through active transport of phospholipids from the exoplasmic to the cytosolic leaflet. Here, we present a total of nine cryo-electron microscopy structures of the human flippase ATP8B1-CDC50A complex at 2.4 to 3.1 Å overall resolution, along with functional and computational studies, addressing the autophosphorylation steps from ATP, substrate recognition and occlusion, as well as a phosphoinositide binding site. We find that the P4-ATPase transport site is occupied by water upon phosphorylation from ATP. Additionally, we identify two different autoinhibited states, a closed and an outward-open conformation. Furthermore, we identify and characterize the PI(3,4,5)P3 binding site of ATP8B1 in an electropositive pocket between transmembrane segments 5, 7, 8, and 10. Our study also highlights the structural basis of a broad lipid specificity of ATP8B1 and adds phosphatidylinositol as a transport substrate for ATP8B1. We report a critical role of the sn-2 ester bond of glycerophospholipids in substrate recognition by ATP8B1 through conserved S403. These findings provide fundamental insights into ATP8B1 catalytic cycle and regulation, and substrate recognition in P4-ATPases.
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Affiliation(s)
- Thibaud Dieudonné
- DANDRITE, Nordic EMBL Partnership for Molecular Medicine, Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
- Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), 91198, Gif-sur-Yvette, France.
| | - Felix Kümmerer
- Structural Biology and NMR Laboratory & Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of Copenhagen, Copenhagen, Denmark
| | - Michelle Juknaviciute Laursen
- DANDRITE, Nordic EMBL Partnership for Molecular Medicine, Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
| | - Charlott Stock
- DANDRITE, Nordic EMBL Partnership for Molecular Medicine, Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
| | - Rasmus Kock Flygaard
- DANDRITE, Nordic EMBL Partnership for Molecular Medicine, Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
| | - Syma Khalid
- Department of Biochemistry, University of Oxford, Oxford, UK
| | - Guillaume Lenoir
- Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), 91198, Gif-sur-Yvette, France
| | - Joseph A Lyons
- Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
- Interdisciplinary Nanoscience Centre (iNANO) Aarhus University, Aarhus, Denmark
| | - Kresten Lindorff-Larsen
- Structural Biology and NMR Laboratory & Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of Copenhagen, Copenhagen, Denmark
| | - Poul Nissen
- DANDRITE, Nordic EMBL Partnership for Molecular Medicine, Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
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20
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Kavallar AM, Mayerhofer C, Aldrian D, Okamoto T, Müller T, Vogel GF. Management and outcomes after liver transplantation for progressive familial intrahepatic cholestasis: A systematic review and meta-analysis. Hepatol Commun 2023; 7:e0286. [PMID: 37756114 PMCID: PMC10531212 DOI: 10.1097/hc9.0000000000000286] [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: 08/07/2023] [Accepted: 08/17/2023] [Indexed: 09/28/2023] Open
Abstract
BACKGROUND Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous rare congenital cholestatic liver disease. Disease progression might necessitate liver transplantation (LT). The aim of this study was to describe the outcome of PFIC1-4 patients after LT. METHODS Electronic databases were searched to identify studies on PFIC and LT. Patients were categorized according to PFIC type, genotype, graft type, age at LT, time of follow-up, and complications and treatment during follow-up. RESULTS Seventy-nine studies with 507 patients met inclusion criteria; most patients were classified as PFIC1-3. The median age at LT was 50 months. The overall 5-year patient survival was 98.5%. PFIC1 patients with diarrhea after LT were at significant risk of developing graft steatosis ( p < 0.0001). Meta-analysis showed an efficacy of 100% [95% CI: 73.9%-100%] for surgical biliary diversion to ameliorate steatosis and 94.9% [95% CI: 53.7%-100%] to improve diarrhea (n = 8). PFIC2 patients with bile salt export pump (BSEP)2 or BSEP3-genotype were at significant risk of developing antibody-induced BSEP deficiency (AIBD) ( p < 0.0001), which was reported in 16.2% of patients at a median of 36.5 months after LT. Meta-analysis showed an efficacy of 81.1% [95% CI: 47.5%-100%] for rituximab-based treatment regimens to improve AIBD (n = 18). HCC was detected in 3.6% of PFIC2 and 13.8% of PFIC4 patients at LT. CONCLUSIONS Fifty percent of PFIC1 patients develop diarrhea and steatosis after LT. Biliary diversion can protect the graft from injury. PFIC2 patients with BSEP2 and BSEP3 genotypes are at significant risk of developing AIBD, and rituximab-based treatment regimens effectively improve AIBD. PFIC3 patients have no PFIC-specific complications following LT.
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Affiliation(s)
- Anna Maria Kavallar
- Department of Paediatrics I, Medical University of Innsbruck, Innsbruck, Austria
| | - Christoph Mayerhofer
- Department of Paediatrics I, Medical University of Innsbruck, Innsbruck, Austria
| | - Denise Aldrian
- Department of Paediatrics I, Medical University of Innsbruck, Innsbruck, Austria
| | - Tatsuya Okamoto
- Department of Pediatric Surgery, Kyoto University Hospital, Kyoto, Japan
| | - Thomas Müller
- Department of Paediatrics I, Medical University of Innsbruck, Innsbruck, Austria
| | - Georg Friedrich Vogel
- Department of Paediatrics I, Medical University of Innsbruck, Innsbruck, Austria
- Institute of Cell Biology, Medical University of Innsbruck, Innsbruck, Austria
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21
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Zheng L, Pan C, Tian W, Liang C, Feng Y, He W, Yang Z, Wang B, Qiu Q, Li N, Sun Y, Qiu H, Sample KM, Zhou L, Zhu X, Hu Y. Atp8a1 deletion increases the proliferative activity of hematopoietic stem cells by impairing PTEN function. Cell Oncol (Dordr) 2023; 46:1069-1083. [PMID: 36930333 DOI: 10.1007/s13402-023-00797-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/05/2023] [Indexed: 03/18/2023] Open
Abstract
PURPOSE The eukaryotic cell plasma membrane contains several asymmetrically distributed phospholipids, which is maintained by the P4-ATPase flippase complex. Herein, we demonstrated the biological effects and mechanisms of asymmetrical loss in hematopoietic stem cells (HSCs). METHODS An Atp8a1 knockout mouse model was employed, from which the HSC (long-term HSCs and short-term HSCs) population was analyzed to assess their abundance and function. Additionally, competitive bone marrow transplantation and 5-FU stress assays were performed. RNA sequencing was performed on Hematopoietic Stem and Progenitor Cells, and DNA damage was assayed using immunofluorescence staining and comet electrophoresis. The protein abundance for members of key signaling pathways was confirmed using western blotting. RESULTS Atp8a1 deletion resulted in slight hyperleukocytosis, associated with the high proliferation of HSCs and BCR/ABL1 transformed leukemia stem cells (LSCs). Atp8a1 deletion increased the repopulation capability of HSCs with a competitive advantage in reconstitution assay. HSCs without Atp8a1 were more sensitive to 5-FU-induced apoptosis. Moreover, Atp8a1 deletion prevented HSC DNA damage and facilitated DNA repair processes. Genes involved in PI3K-AKT-mTORC1, DNA repair, and AP-1 complex signaling were enriched and elevated in HSCs with Atp8a1 deletion. Furthermore, Atp8a1 deletion caused decreased PTEN protein levels, resulting in the activation of PI3K-AKT-mTORC1 signaling, further increasing the activity of JNK/AP-1 signaling and YAP1 phosphorylation. CONCLUSION We identified the role of Atp8a1 on hematopoiesis and HSCs. Atp8a1 deletion resulted in the loss of phosphatidylserine asymmetry and intracellular signal transduction chaos.
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Affiliation(s)
- Li Zheng
- Department of Thyroid Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, No.17, Ren-Min-Nan Road (Third Section), Chengdu, 610041, Sichuan, China
| | - Cong Pan
- Department of Thyroid Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, No.17, Ren-Min-Nan Road (Third Section), Chengdu, 610041, Sichuan, China
| | - Wanli Tian
- The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, Sichuan, China
| | - Cailing Liang
- Department of Thyroid Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, No.17, Ren-Min-Nan Road (Third Section), Chengdu, 610041, Sichuan, China
| | - Yunyu Feng
- Department of Thyroid Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, No.17, Ren-Min-Nan Road (Third Section), Chengdu, 610041, Sichuan, China
| | - Wei He
- Department of Thyroid Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, No.17, Ren-Min-Nan Road (Third Section), Chengdu, 610041, Sichuan, China
| | - Zirong Yang
- Institute of Life Science, eBond Pharmaceutical Technology Ltd., Chengdu, China
| | - Bochuan Wang
- Department of Thyroid Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, No.17, Ren-Min-Nan Road (Third Section), Chengdu, 610041, Sichuan, China
| | - Qiang Qiu
- Department of Thyroid Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, No.17, Ren-Min-Nan Road (Third Section), Chengdu, 610041, Sichuan, China
| | - Ning Li
- Department of Thyroid Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, No.17, Ren-Min-Nan Road (Third Section), Chengdu, 610041, Sichuan, China
| | - Yuanyuan Sun
- Department of Thyroid Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, No.17, Ren-Min-Nan Road (Third Section), Chengdu, 610041, Sichuan, China
| | - Huandi Qiu
- Department of Thyroid Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, No.17, Ren-Min-Nan Road (Third Section), Chengdu, 610041, Sichuan, China
| | - Klarke M Sample
- Institute of Life Science, eBond Pharmaceutical Technology Ltd., Chengdu, China
| | - Lingyun Zhou
- Department of Thyroid Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, No.17, Ren-Min-Nan Road (Third Section), Chengdu, 610041, Sichuan, China.
- Center of Infectious Diseases, West China Hospital of Sichuan University, 37 GuoXue Lane, Chengdu, 610041, Sichuan Province, China.
| | - Xianjun Zhu
- The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, Sichuan, China.
| | - Yiguo Hu
- Department of Thyroid Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, No.17, Ren-Min-Nan Road (Third Section), Chengdu, 610041, Sichuan, China.
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22
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Chen CB, Hsu JS, Chen PL, Wu JF, Li HY, Liou BY, Chang MH, Ni YH, Hwu WL, Chien YH, Chou YY, Yang YJ, Lee NC, Chen HL. Combining Panel-Based Next-Generation Sequencing and Exome Sequencing for Genetic Liver Diseases. J Pediatr 2023; 258:113408. [PMID: 37019333 DOI: 10.1016/j.jpeds.2023.113408] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 12/02/2022] [Accepted: 03/25/2023] [Indexed: 04/07/2023]
Abstract
OBJECTIVES To determine how advanced genetic analysis methods may help in clinical diagnosis. STUDY DESIGN We report a combined genetic diagnosis approach for patients with clinical suspicion of genetic liver diseases in a tertiary referral center, using tools either tier 1: Sanger sequencing on SLC2SA13, ATP8B1, ABCB11, ABCB4, and JAG1 genes, tier 2: panel-based next generation sequencing (NGS), or tier 3: whole-exome sequencing (WES) analysis. RESULTS In a total of 374 patients undergoing genetic analysis, 175 patients received tier 1 Sanger sequencing based on phenotypic suspicion, and pathogenic variants were identified in 38 patients (21.7%). Tier 2 included 216 patients (39 of tier 1-negative patients) who received panel-based NGS, and pathogenic variants were identified in 60 (27.8%). In tier 3, 41 patients received WES analysis, and 20 (48.8%) obtained genetic diagnosis. Pathogenic variants were detected in 6 of 19 (31.6%) who tested negative in tier 2, and a greater detection rate in 14 of 22 (63.6%) patients with deteriorating/multiorgan disease receiving one-step WES (P = .041). The overall disease spectrum is comprised of 35 genetic defects; 90% of genes belong to the functional categories of small molecule metabolism, ciliopathy, bile duct development, and membrane transport. Only 13 (37%) genetic diseases were detected in more than 2 families. A hypothetical approach using a small panel-based NGS can serve as the first tier with diagnostic yield of 27.8% (98/352). CONCLUSIONS NGS based genetic test using a combined panel-WES approach is efficient for the diagnosis of the highly diverse genetic liver diseases.
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Affiliation(s)
- Chi-Bo Chen
- Department of Pediatrics, National Taiwan University College of Medicine and Children's Hospital, Taipei, Taiwan
| | - Jacob Shujui Hsu
- Graduate Institute of Medical Genomics and Proteomics, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Pei-Lung Chen
- Graduate Institute of Medical Genomics and Proteomics, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Jia-Feng Wu
- Department of Pediatrics, National Taiwan University College of Medicine and Children's Hospital, Taipei, Taiwan
| | - Huei-Ying Li
- Medical Microbiome Center, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Bang-Yu Liou
- Department of Pediatrics, National Taiwan University College of Medicine and Children's Hospital, Taipei, Taiwan
| | - Mei-Hwei Chang
- Department of Pediatrics, National Taiwan University College of Medicine and Children's Hospital, Taipei, Taiwan
| | - Yen-Hsuan Ni
- Department of Pediatrics, National Taiwan University College of Medicine and Children's Hospital, Taipei, Taiwan; Medical Microbiome Center, National Taiwan University College of Medicine, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Wuh-Liang Hwu
- Department of Pediatrics, National Taiwan University College of Medicine and Children's Hospital, Taipei, Taiwan; Graduate Institute of Medical Genomics and Proteomics, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan
| | - Yin-Hsiu Chien
- Department of Pediatrics, National Taiwan University College of Medicine and Children's Hospital, Taipei, Taiwan; Graduate Institute of Medical Genomics and Proteomics, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan
| | - Yen-Yin Chou
- Department of Pediatrics, National Cheng Kung University Hospital, Taipei, Taiwan
| | - Yao-Jong Yang
- Department of Pediatrics, National Cheng Kung University Hospital, Taipei, Taiwan
| | - Ni-Chung Lee
- Department of Pediatrics, National Taiwan University College of Medicine and Children's Hospital, Taipei, Taiwan; Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan
| | - Huey-Ling Chen
- Department of Pediatrics, National Taiwan University College of Medicine and Children's Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan; Department of Medical Education & Bioethics, National Taiwan University College of Medicine, Taipei, Taiwan.
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23
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Kavallar AM, Messner F, Scheidl S, Oberhuber R, Schneeberger S, Aldrian D, Berchtold V, Sanal M, Entenmann A, Straub S, Gasser A, Janecke AR, Müller T, Vogel GF. Internal Ileal Diversion as Treatment for Progressive Familial Intrahepatic Cholestasis Type 1-Associated Graft Inflammation and Steatosis after Liver Transplantation. CHILDREN (BASEL, SWITZERLAND) 2022; 9:children9121964. [PMID: 36553407 PMCID: PMC9777440 DOI: 10.3390/children9121964] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 12/07/2022] [Accepted: 12/12/2022] [Indexed: 12/16/2022]
Abstract
BACKGROUND Progressive Familial Intrahepatic cholestasis type I (PFIC1) is a rare congenital hepatopathy causing cholestasis with progressive liver disease. Surgical interruption of the enterohepatic circulation, e.g., surgical biliary diversion (SBD) can slow down development of liver cirrhosis. Eventually, end stage liver disease necessitates liver transplantation (LT). PFIC1 patients might develop diarrhea, graft steatosis and inflammation after LT. SBD after LT was shown to be effective in the alleviation of liver steatosis and graft injury. CASE REPORT Three PFIC1 patients received LT at the ages of two, two and a half and five years. Shortly after LT diarrhea and graft steatosis was recognized, SBD to the terminal ileum was opted to prevent risk for ascending cholangitis. After SBD, inflammation and steatosis was found to be reduced to resolved, as seen by liver biochemistry and ultrasounds. Diarrhea was reported unchanged. CONCLUSION We present three PFIC1 cases for whom SBD to the terminal ileum successfully helped to resolve graft inflammation and steatosis.
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Affiliation(s)
- Anna M. Kavallar
- Department of Paediatrics I, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Franka Messner
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Stefan Scheidl
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Rupert Oberhuber
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Stefan Schneeberger
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Denise Aldrian
- Department of Paediatrics I, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Valeria Berchtold
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Murat Sanal
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Andreas Entenmann
- Department of Paediatrics I, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Simon Straub
- Department of Paediatrics I, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Anna Gasser
- Department of Paediatrics I, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Andreas R. Janecke
- Department of Paediatrics I, Medical University of Innsbruck, 6020 Innsbruck, Austria
- Institute of Human Genetics, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Thomas Müller
- Department of Paediatrics I, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Georg F. Vogel
- Department of Paediatrics I, Medical University of Innsbruck, 6020 Innsbruck, Austria
- Institute of Cell Biology, Biocenter, Medical University of Innsbruck, 6020 Innsbruck, Austria
- Correspondence: ; Tel.: +43-(0)-512-504-23501; Fax: +43-(0)-512-504-23491
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24
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Gómez-Mellado VE, Ho-Mok KS, van der Mark VA, van der Wel NN, Grootemaat AE, Verhoeven AJ, Elferink RPJO, Paulusma CC. The phospholipid flippase ATP8B1 is required for lysosomal fusion in macrophages. Cell Biochem Funct 2022; 40:914-925. [PMID: 36169099 PMCID: PMC10087937 DOI: 10.1002/cbf.3752] [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: 04/20/2022] [Revised: 09/08/2022] [Accepted: 09/12/2022] [Indexed: 12/15/2022]
Abstract
ATP8B1 is a phospholipid flippase and member of the type 4 subfamily of P-type ATPases (P4-ATPase) subfamily. P4-ATPases catalyze the translocation of phospholipids across biological membranes, ensuring proper membrane asymmetry, which is crucial for membrane protein targeting and activity, vesicle biogenesis, and barrier function. Here we have investigated the role of ATP8B1 in the endolysosomal pathway in macrophages. Depletion of ATP8B1 led to delayed degradation of content in the phagocytic pathway and in overacidification of the endolysosomal system. Furthermore, ATP8B1 knockdown cells exhibited large multivesicular bodies filled with intraluminal vesicles. Similar phenotypes were observed in CRISPR-generated ATP8B1 knockout cells. Importantly, induction of autophagy led to accumulation of autophagosomes in ATP8B1 knockdown cells. Collectively, our results support a novel role for ATP8B1 in lysosomal fusion in macrophages, a process crucial in the terminal phase of endolysosomal degradation.
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Affiliation(s)
- Valentina E Gómez-Mellado
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Kam S Ho-Mok
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Vincent A van der Mark
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Nicole N van der Wel
- Department of Medical Biology, Electron Microscopy Center Amsterdam, Amsterdam University Medical Center, Amsterdam, The Netherlands
| | - Anita E Grootemaat
- Department of Medical Biology, Electron Microscopy Center Amsterdam, Amsterdam University Medical Center, Amsterdam, The Netherlands
| | - Arthur J Verhoeven
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Ronald P J Oude Elferink
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Coen C Paulusma
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
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25
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Jain BK, Wagner AS, Reynolds TB, Graham TR. Lipid Transport by Candida albicans Dnf2 Is Required for Hyphal Growth and Virulence. Infect Immun 2022; 90:e0041622. [PMID: 36214556 PMCID: PMC9670988 DOI: 10.1128/iai.00416-22] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Accepted: 09/19/2022] [Indexed: 11/20/2022] Open
Abstract
Candida albicans is a common cause of human mucosal yeast infections, and invasive candidiasis can be fatal. Antifungal medications are limited, but those targeting the pathogen cell wall or plasma membrane have been effective. Therefore, virulence factors controlling membrane biogenesis are potential targets for drug development. P4-ATPases contribute to membrane biogenesis by selecting and transporting specific lipids from the extracellular leaflet to the cytoplasmic leaflet of the bilayer to generate lipid asymmetry. A subset of heterodimeric P4-ATPases, including Dnf1-Lem3 and Dnf2-Lem3 from Saccharomyces cerevisiae, transport phosphatidylcholine (PC), phosphatidylethanolamine (PE), and the sphingolipid glucosylceramide (GlcCer). GlcCer is a critical lipid for Candida albicans polarized growth and virulence, but the role of GlcCer transporters in virulence has not been explored. Here, we show that the Candida albicans Dnf2 (CaDnf2) requires association with CaLem3 to form a functional transporter and flip fluorescent derivatives of GlcCer, PC, and PE across the plasma membrane. Mutation of conserved substrate-selective residues in the membrane domain strongly abrogates GlcCer transport and partially disrupts PC transport by CaDnf2. Candida strains harboring dnf2-null alleles (dnf2ΔΔ) or point mutations that disrupt substrate recognition exhibit defects in yeast-to-hypha growth transition, filamentous growth, and virulence in systemically infected mice. The influence of CaDNF1 deletion on the morphological phenotypes is negligible, although the dnf1ΔΔ dnf2ΔΔ strain was less virulent than the dnf2ΔΔ strain. These results indicate that the transport of GlcCer and/or PC by plasma membrane P4-ATPases is important for the pathogenicity of Candida albicans.
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Affiliation(s)
- Bhawik K. Jain
- Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee, USA
| | - Andrew S. Wagner
- Department of Microbiology, University of Tennessee, Knoxville, Tennessee, USA
| | - Todd B. Reynolds
- Department of Microbiology, University of Tennessee, Knoxville, Tennessee, USA
| | - Todd R. Graham
- Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee, USA
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26
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Bedoyan SM, Lovell OT, Horslen SP, Squires JE. Odevixibat: a promising new treatment for progressive familial intrahepatic cholestasis. Expert Opin Pharmacother 2022; 23:1771-1779. [PMID: 36278881 PMCID: PMC10074157 DOI: 10.1080/14656566.2022.2140040] [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: 06/13/2022] [Accepted: 10/21/2022] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Progressive familial intrahepatic cholestasis (PFIC) refers to a group of heterogeneous, mostly autosomal recessive disorders resulting from the inability to properly form and excrete bile from hepatocytes. The resulting shared phenotype is one of hepatocellular cholestasis. Clinical management targeting refractory itch and surgical interventions to interrupt the enterohepatic circulation are often pursued with variable efficacy. Recent development of the family of IBAT inhibitor therapeutics has introduced a novel tool in the armamentarium for the treatment of PFIC. AREAS COVERED Data from Phase 3 and 3 clinical trials were reviewed. The primary endpoints in most studies included effect on pruritus, serum bile acid levels, and quality of life metrics, with the duration of the study ranging between 24 and 72 weeks. Most common adverse events included diarrhea, vomiting, and elevation in transaminases. EXPERT OPINION IBAT inhibition with therapeutics such as odevibixat have shown that it is well-tolerated and efficacious in mitigating itch and reducing serum bile acid levels. While the few early published trials with odevixibat have shown good efficacy, what remains to be seen is long-term, sustainable improvement and if or how these medications will supplement or replace the current medical and surgical therapies available for managing PFIC disorders.
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Affiliation(s)
- Sarah M. Bedoyan
- Department of Pediatrics, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Olya T. Lovell
- Department of Pharmacy, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Simon P. Horslen
- Division of Gastroenterology and Hepatology, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - James E. Squires
- Division of Gastroenterology and Hepatology, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA
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27
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Gómez-Mellado VE, Chang JC, Ho-Mok KS, Bernardino Morcillo C, Kersten RHJ, Oude Elferink RPJ, Verhoeven AJ, Paulusma CC. ATP8B1 Deficiency Results in Elevated Mitochondrial Phosphatidylethanolamine Levels and Increased Mitochondrial Oxidative Phosphorylation in Human Hepatoma Cells. Int J Mol Sci 2022; 23:ijms232012344. [PMID: 36293199 PMCID: PMC9604224 DOI: 10.3390/ijms232012344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 10/11/2022] [Accepted: 10/12/2022] [Indexed: 11/20/2022] Open
Abstract
ATP8B1 is a phospholipid flippase that is deficient in patients with progressive familial intrahepatic cholestasis type 1 (PFIC1). PFIC1 patients suffer from severe liver disease but also present with dyslipidemia, including low plasma cholesterol, of yet unknown etiology. Here we show that ATP8B1 knockdown in HepG2 cells leads to a strong increase in the mitochondrial oxidative phosphorylation (OXPHOS) without a change in glycolysis. The enhanced OXPHOS coincides with elevated low-density lipoprotein receptor protein and increased mitochondrial fragmentation and phosphatidylethanolamine levels. Furthermore, expression of phosphatidylethanolamine N-methyltransferase, an enzyme that catalyzes the conversion of mitochondrial-derived phosphatidylethanolamine to phosphatidylcholine, was reduced in ATP8B1 knockdown cells. We conclude that ATP8B1 deficiency results in elevated mitochondrial PE levels that stimulate mitochondrial OXPHOS. The increased OXPHOS leads to elevated LDLR levels, which provides a possible explanation for the reduced plasma cholesterol levels in PFIC1 disease.
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Affiliation(s)
- Valentina E. Gómez-Mellado
- Amsterdam UMC, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Meibergdreef 69, 1105 BK Amsterdam, The Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, 1105 AZ Amsterdam, The Netherlands
| | - Jung-Chin Chang
- Amsterdam UMC, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Meibergdreef 69, 1105 BK Amsterdam, The Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, 1105 AZ Amsterdam, The Netherlands
- Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, 3584 CS Utrecht, The Netherlands
| | - Kam S. Ho-Mok
- Amsterdam UMC, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Meibergdreef 69, 1105 BK Amsterdam, The Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, 1105 AZ Amsterdam, The Netherlands
| | - Carmen Bernardino Morcillo
- Amsterdam UMC, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Meibergdreef 69, 1105 BK Amsterdam, The Netherlands
| | - Remco H. J. Kersten
- Amsterdam UMC, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Meibergdreef 69, 1105 BK Amsterdam, The Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, 1105 AZ Amsterdam, The Netherlands
| | - Ronald P. J. Oude Elferink
- Amsterdam UMC, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Meibergdreef 69, 1105 BK Amsterdam, The Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, 1105 AZ Amsterdam, The Netherlands
| | - Arthur J. Verhoeven
- Amsterdam UMC, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Meibergdreef 69, 1105 BK Amsterdam, The Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, 1105 AZ Amsterdam, The Netherlands
| | - Coen C. Paulusma
- Amsterdam UMC, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Meibergdreef 69, 1105 BK Amsterdam, The Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, 1105 AZ Amsterdam, The Netherlands
- Correspondence:
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28
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Nayagam JS, Foskett P, Strautnieks S, Agarwal K, Miquel R, Joshi D, Thompson RJ. Clinical phenotype of adult-onset liver disease in patients with variants in ABCB4, ABCB11, and ATP8B1. Hepatol Commun 2022; 6:2654-2664. [PMID: 35894240 PMCID: PMC9512461 DOI: 10.1002/hep4.2051] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 05/17/2022] [Accepted: 05/31/2022] [Indexed: 11/26/2022] Open
Abstract
Variants in ATP8B1, ABCB11, and ABCB4 underlie the most prevalent forms of progressive familial intrahepatic cholestasis. We aim to describe variants in these genes in a cohort of patients with adult-onset liver disease, and explore a genotype-phenotype correlation. Patients with onset of liver disease aged above 18 who underwent sequencing of cholestasis genes for clinical purposes over a 5-year period were identified. Bioinformatic analysis of variants was performed. Liver histology was evaluated in patients with variants. Of the 356 patients tested, at least one variant was identified in 101 (28.4%): 46 ABCB4, 35 ABCB11, and 28 ATP8B1. Patients with ABCB4 variants had chronic liver disease (71.7%) and pregnancy-associated liver dysfunction (75%), with a younger age of onset in more severe genotypes (p = 0.046). ABCB11 variants presented with pregnancy-associated liver dysfunction (82.4%) and acute/episodic cholestasis (40%), with no association between age of onset and genotype severity. ATP8B1 variants were associated with chronic liver disease (75%); however, they were commonly seen in patients with an alternate etiology of liver disease and variants were of low predicted pathogenicity. In adults with suspected genetic cholestasis, variants in cholestasis genes were frequently identified and were likely to contribute to the development of liver disease, particularly ABCB4 and ABCB11. Variants were often in heterozygous state, and they should no longer be considered recessive Mendelian traits. Sequencing cholestasis genes in selected patients with adult-onset disease should be considered, with interpretation in close collaboration with histopathologists and geneticists.
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Affiliation(s)
- Jeremy S. Nayagam
- Institute of Liver StudiesKing's College HospitalLondonUK
- Institute of Liver Studies, Immunology & Microbial SciencesKing's College LondonLondonUK
| | - Pierre Foskett
- Institute of Liver StudiesKing's College HospitalLondonUK
| | | | - Kosh Agarwal
- Institute of Liver StudiesKing's College HospitalLondonUK
| | - Rosa Miquel
- Liver Histopathology LaboratoryInstitute of Liver StudiesKing's College HospitalLondonUK
| | - Deepak Joshi
- Institute of Liver StudiesKing's College HospitalLondonUK
| | - Richard J. Thompson
- Institute of Liver StudiesKing's College HospitalLondonUK
- Institute of Liver Studies, Immunology & Microbial SciencesKing's College LondonLondonUK
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29
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Shin HW, Takatsu H. Regulatory Roles of N- and C-Terminal Cytoplasmic Regions of P4-ATPases. Chem Pharm Bull (Tokyo) 2022; 70:524-532. [DOI: 10.1248/cpb.c22-00042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- Hye-Won Shin
- Graduate School of Pharmaceutical Sciences, Kyoto University
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30
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Ibrahim SH, Kamath BM, Loomes KM, Karpen SJ. Reply. Hepatology 2022; 76:E47. [PMID: 35384005 DOI: 10.1002/hep.32493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 03/18/2022] [Indexed: 12/08/2022]
Affiliation(s)
- Samar H Ibrahim
- Division of Pediatric Gastroenterology, Mayo Clinic, Rochester, Minnesota, USA
| | - Binita M Kamath
- The Hospital for Sick Children and the University of Toronto, Toronto, Ontario, Canada
| | - Kathleen M Loomes
- The Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Saul J Karpen
- Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, Georgia, USA
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31
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Vitale G, Mattiaccio A, Conti A, Turco L, Seri M, Piscaglia F, Morelli MC. Genetics in Familial Intrahepatic Cholestasis: Clinical Patterns and Development of Liver and Biliary Cancers: A Review of the Literature. Cancers (Basel) 2022; 14:cancers14143421. [PMID: 35884482 PMCID: PMC9322180 DOI: 10.3390/cancers14143421] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 07/10/2022] [Accepted: 07/12/2022] [Indexed: 02/06/2023] Open
Abstract
The family of inherited intrahepatic cholestasis includes autosomal recessive cholestatic rare diseases of childhood involved in bile acids secretion or bile transport defects. Specific genetic pathways potentially cause many otherwise unexplained cholestasis or hepatobiliary tumours in a healthy liver. Lately, next-generation sequencing and whole-exome sequencing have improved the diagnostic procedures of familial intrahepatic cholestasis (FIC), as well as the discovery of several genes responsible for FIC. Moreover, mutations in these genes, even in the heterozygous status, may be responsible for cryptogenic cholestasis in both young and adults. Mutations in FIC genes can influence serum and hepatic levels of bile acids. Experimental studies on the NR1H4 gene have shown that high bile acids concentrations cause excessive production of inflammatory cytokines, resistance to apoptosis, and increased cell regeneration, all risk conditions for developing hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). NR1H4 gene encodes farnesoid X-activated receptor having a pivotal role in bile salts synthesis. Moreover, HCC and CCA can emerge in patients with several FIC genes such as ABCB11, ABCB4 and TJP2. Herein, we reviewed the available data on FIC-related hepatobiliary cancers, reporting on genetics to the pathophysiology, the risk factors and the clinical presentation.
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Affiliation(s)
- Giovanni Vitale
- Internal Medicine Unit for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (L.T.); (M.C.M.)
- Correspondence:
| | - Alessandro Mattiaccio
- U.O. Genetica Medica, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.M.); (A.C.); (M.S.)
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum-University di Bologna, 40138 Bologna, Italy
| | - Amalia Conti
- U.O. Genetica Medica, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.M.); (A.C.); (M.S.)
| | - Laura Turco
- Internal Medicine Unit for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (L.T.); (M.C.M.)
| | - Marco Seri
- U.O. Genetica Medica, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (A.M.); (A.C.); (M.S.)
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum-University di Bologna, 40138 Bologna, Italy
| | - Fabio Piscaglia
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy;
| | - Maria Cristina Morelli
- Internal Medicine Unit for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (L.T.); (M.C.M.)
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Ibrahim SH, Kamath BM, Loomes KM, Karpen SJ. Cholestatic liver diseases of genetic etiology: Advances and controversies. Hepatology 2022; 75:1627-1646. [PMID: 35229330 DOI: 10.1002/hep.32437] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 02/09/2022] [Accepted: 02/11/2022] [Indexed: 12/14/2022]
Abstract
With the application of modern investigative technologies, cholestatic liver diseases of genetic etiology are increasingly identified as the root cause of previously designated "idiopathic" adult and pediatric liver diseases. Here, we review advances in the field enhanced by a deeper understanding of the phenotypes associated with specific gene defects that lead to cholestatic liver diseases. There are evolving areas for clinicians in the current era specifically regarding the role for biopsy and opportunities for a "sequencing first" approach. Risk stratification based on the severity of the genetic defect holds promise to guide the decision to pursue primary liver transplantation versus medical therapy or nontransplant surgery, as well as early screening for HCC. In the present era, the expanding toolbox of recently approved therapies for hepatologists has real potential to help many of our patients with genetic causes of cholestasis. In addition, there are promising agents under study in the pipeline. Relevant to the current era, there are still gaps in knowledge of causation and pathogenesis and lack of fully accepted biomarkers of disease progression and pruritus. We discuss strategies to overcome the challenges of genotype-phenotype correlation and draw attention to the extrahepatic manifestations of these diseases. Finally, with attention to identifying causes and treatments of genetic cholestatic disorders, we anticipate a vibrant future of this dynamic field which builds upon current and future therapies, real-world evaluations of individual and combined therapeutics, and the potential incorporation of effective gene editing and gene additive technologies.
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Affiliation(s)
- Samar H Ibrahim
- Division of Pediatric GastroenterologyMayo ClinicRochesterMinnesotaUSA
| | - Binita M Kamath
- The Hospital for Sick ChildrenUniversity of TorontoTorontoOntarioCanada
| | - Kathleen M Loomes
- The Children's Hospital of Philadelphia and Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Saul J Karpen
- Emory University School of Medicine and Children's Healthcare of AtlantaAtlantaGeorgiaUSA
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Leroy A, Perrin H, Porret R, Sempoux C, Chtioui H, Fraga M, Bart PA. Iberogast®-Induced Acute Liver Injury-A Case Report. GASTRO HEP ADVANCES 2022; 1:601-603. [PMID: 39132058 PMCID: PMC11308012 DOI: 10.1016/j.gastha.2022.02.020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 02/16/2022] [Indexed: 08/13/2024]
Abstract
Alternative medicines such as phytotherapy and herbal preparations have been widely used over the past 5 decades. However, they are still poorly known in Western medicine, and because they are considered as natural products, they are often omitted in the review of medication. One of the most used herbal preparations in Europe is Iberogast®, a formulation of 9 medicinal plant extracts, including Greater Celandine that has proven effective in the treatment of functional dyspepsia and irritable bowel syndrome. Safety and tolerability of Iberogast® were extensively evaluated in double-blind and randomized studies vs placebo, but rare and usually mild adverse symptoms have been reported in the literature. We report a 32-year-old female with no previous medical history who presented to the emergency department with abdominal pain, jaundice, and pruritus. The blood tests revealed an acute severe hepatitis with marked increase of direct bilirubin. After exclusion of other possible acute liver injury etiologies, we retained the diagnosis of Iberogast®-associated drug-induced liver injury. Patient's symptoms resolved spontaneously 5 weeks after treatment interruption. Despite the general safety of Iberogast®, occasional cases of drug-induced liver injury have been documented. Based on these observations, we recommend that the use of herbal and phytotherapeutic products should be part of the standard investigation of the medical history, as they could be relevant information in the diagnosis process of acute liver injury.
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Affiliation(s)
- Alice Leroy
- Service de Médecine interne, CHUV, Lausanne, Switzerland
| | - Henri Perrin
- Service de Médecine interne, CHUV, Lausanne, Switzerland
| | - Raphael Porret
- Service de Médecine interne, CHUV, Lausanne, Switzerland
| | | | - Haithem Chtioui
- Service de Pharmacologie clinique, CHUV, Lausanne, Switzerland
| | - Montserrat Fraga
- Service de Gastro-entérologie et d’hépatologie, CHUV, Lausanne, Switzerland
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Ileal Bile Acid Transporter Inhibition Reduces Post-Transplant Diarrhea and Growth Failure in FIC1 Disease—A Case Report. CHILDREN 2022; 9:children9050669. [PMID: 35626847 PMCID: PMC9139332 DOI: 10.3390/children9050669] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 04/07/2022] [Accepted: 05/03/2022] [Indexed: 12/12/2022]
Abstract
Familial intrahepatic cholestasis 1 (FIC1) disease is a genetic disorder characterized by hepatic and gastrointestinal disease due to ATP8B1 deficiency, often requiring liver transplantation (LT). Extrahepatic symptoms, such as diarrhea, malabsorption, and failure to thrive, do not improve and instead may be aggravated after LT. We describe a patient with FIC1 disease who underwent LT at 2 years, 8 months of age. After LT, the child developed severe refractory diarrhea and failed to thrive. The response to bile acid resins was unsatisfactory, and the parents declined our recommendation for partial external biliary diversion (PEBD). Quality of life was extremely impaired, especially due to severe diarrhea, making school attendance impossible. Attempting to reduce the total bile acids, we initiated off-label use of the ileal bile acid transporter (IBAT) inhibitor Elobixibat (Goofice™), later converted to Odevixibat (Bylvay™). After six months of treatment, the patient showed less stool output, increased weight and height, and improved physical energy levels. The child could now pursue higher undergraduate education. In our patient with FIC1 disease, the use of IBAT inhibitors was effective in treating chronic diarrhea and failure to thrive. This approach is novel; further investigations are needed to clarify the exact mode of action in this condition.
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MYO5B Gene Mutations: A Not Negligible Cause of Intrahepatic Cholestasis of Infancy With Normal Gamma-Glutamyl Transferase Phenotype. J Pediatr Gastroenterol Nutr 2022; 74:e115-e121. [PMID: 35129155 DOI: 10.1097/mpg.0000000000003399] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVES Progressive familial intrahepatic cholestasis is an expanding group of autosomal recessive intrahepatic cholestatic disorders. Recently, next-generation sequencing allowed identifying new genes responsible for new specific disorders. Two biochemical phenotypes have been identified according to gamma-glutamyltransferase (GGT) activity. Mutations of the myosin 5B gene (MYO5B) are known to cause microvillus inclusion disease. Recently, different mutations in MYO5B gene have been reported in patients with low-GGT cholestasis. METHODS A multicenter retrospective and prospective study was conducted in 32 children with cryptogenic intrahepatic cholestasis. Clinical, biochemical, histological, and treatment data were analyzed in these patients. DNA from peripheral blood was extracted, and all patients were studied by whole exome sequencing followed by Sanger sequencing. RESULTS Six patients out of 32 had mutations in the MYO5B gene. Of these six patients, the median age at disease onset was 0.8 years, and the median length of follow-up was 4.2 years. The most common signs were pruritus, poor growth, hepatomegaly, jaundice, and hypocholic stools. Two patients also showed intestinal involvement. Transaminases and conjugated bilirubin were moderately increased, serum bile acids elevated, and GGT persistently normal. At anti-Myo5B immunostaining, performed in liver biopsy of two patients, coarse granules were evident within the cytoplasm of hepatocytes while bile salt export pump was normally expressed at the canalicular membrane. Six variants in homozygosity or compound heterozygosity in the MYO5B gene were identified, and three of them have never been described before. All nucleotide alterations were located on the myosin motor domain except one missense variant found in the isoleucine-glutamine calmodulin-binding motif. CONCLUSIONS We identified causative mutations in MYO5B in 18.7% of a selected cohort of patients with intrahepatic cholestasis confirming a relevant role for the MYO5B gene in low-GGT cholestasis.
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36
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Pfister ED, Dröge C, Liebe R, Stalke A, Buhl N, Ballauff A, Cantz T, Bueltmann E, Stindt J, Luedde T, Baumann U, Keitel V. Extrahepatic manifestations of progressive familial intrahepatic cholestasis syndromes: Presentation of a case series and literature review. Liver Int 2022; 42:1084-1096. [PMID: 35184362 DOI: 10.1111/liv.15200] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 02/02/2022] [Accepted: 02/11/2022] [Indexed: 02/13/2023]
Abstract
BACKGROUND AND AIMS Progressive familial intrahepatic cholestasis (PFIC) is a collective term for a heterogenous group of rare, inherited cholestasis syndromes. The number of genes underlying the clinical PFIC phenotype is still increasing. While progressive liver disease and its sequelae such as portal hypertension, pruritus and hepatocellular carcinoma determine transplant-free survival, extrahepatic manifestations may cause relevant morbidity. METHODS We performed a literature search for extrahepatic manifestations of PFIC associated with pathogenic gene variants in ATP8B1, ABCB11, ABCB4, TJP2, NR1H4 and MYO5B. To illustrate the extrahepatic symptoms described in the literature, PFIC cases from our centres were revisited. RESULTS Extrahepatic symptoms are common in PFIC subtypes, where the affected gene is expressed at high levels in other tissues. While most liver-associated complications resolve after successful orthotopic liver transplantation (OLT), some extrahepatic symptoms show no response or even worsen after OLT. CONCLUSION The spectrum of extrahepatic manifestations in PFIC highlights essential, non-redundant roles of the affected genes in other organs. Extrahepatic features contribute towards low health-related quality of life (HRQOL) and morbidity in PFIC. While OLT is often the only remaining, curative treatment, potential extrahepatic manifestations need to be carefully monitored and addressed.
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Affiliation(s)
- Eva-Doreen Pfister
- Division of Paediatric Gastroenterology and Hepatology, Department of Paediatric Liver, Kidney and Metabolic Diseases, Hannover Medical School, Hannover, Germany
| | - Carola Dröge
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany.,Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Magdeburg, Medical Faculty of Otto von Guericke University, Magdeburg, Germany
| | - Roman Liebe
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Amelie Stalke
- Division of Paediatric Gastroenterology and Hepatology, Department of Paediatric Liver, Kidney and Metabolic Diseases, Hannover Medical School, Hannover, Germany.,Department of Human Genetics, Hannover Medical School, Hannover, Germany
| | - Nicole Buhl
- Division of Paediatric Gastroenterology and Hepatology, Department of Paediatric Liver, Kidney and Metabolic Diseases, Hannover Medical School, Hannover, Germany.,Department of Human Genetics, Hannover Medical School, Hannover, Germany
| | - Antje Ballauff
- Department of Paediatrics, Helios Hospital, Krefeld, Germany
| | - Tobias Cantz
- Translational Hepatology and Stem Cell Biology, Department of Gastroenterology, Hepatology and Endocrinology, REBIRTH-Center for Translational Regenerative Medicine, Hannover Medical School, Hannover, Germany
| | - Eva Bueltmann
- Institute of Diagnostic and Interventional Neuroradiology, Hannover Medical School, Hannover, Germany
| | - Jan Stindt
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Tom Luedde
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Ulrich Baumann
- Division of Paediatric Gastroenterology and Hepatology, Department of Paediatric Liver, Kidney and Metabolic Diseases, Hannover Medical School, Hannover, Germany.,Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Verena Keitel
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany.,Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Magdeburg, Medical Faculty of Otto von Guericke University, Magdeburg, Germany
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37
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Suzuki H, Arinaga-Hino T, Sano T, Mihara Y, Kusano H, Mizuochi T, Togawa T, Ito S, Ide T, Kuwahara R, Amano K, Kawaguchi T, Yano H, Kage M, Koga H, Torimura T. Case Report: A Rare Case of Benign Recurrent Intrahepatic Cholestasis-Type 1 With a Novel Heterozygous Pathogenic Variant of ATP8B1. Front Med (Lausanne) 2022; 9:891659. [PMID: 35572954 PMCID: PMC9099094 DOI: 10.3389/fmed.2022.891659] [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: 03/08/2022] [Accepted: 04/07/2022] [Indexed: 12/15/2022] Open
Abstract
Benign recurrent intrahepatic cholestasis type 1 (BRIC1) is a rare autosomal recessive disorder that is characterized by intermittent episodes of jaundice and intense pruritus and caused by pathogenic variants of adenosine triphosphatase phospholipid transporting 8B1 (ATP8B1). The presence of genetic heterogeneity in the variants of ATP8B1 is suggested. Herein, we describe a unique clinical course in a patient with BRIC1 and a novel heterozygous pathogenic variant of ATP8B1. A 20-year-old Japanese man experienced his first cholestasis attack secondary to elevated transaminase at 17 years of age. Laboratory examinations showed no evidence of liver injury caused by viral, autoimmune, or inborn or acquired metabolic etiologies. Since the patient also had elevated transaminase and hypoalbuminemia, he was treated with ursodeoxycholic acid and prednisolone. However, these treatments did not relieve his symptoms. Histopathological assessment revealed marked cholestasis in the hepatocytes, Kupffer cells, and bile canaliculi, as well as a well-preserved intralobular bile duct arrangement and strongly expressed bile salt export pump at the canalicular membrane. Targeted next-generation sequencing detected a novel heterozygous pathogenic variant of ATP8B1 (c.1429 + 2T > G). Taken together, the patient was highly suspected of having BRIC1. Ultimately, treatment with 450 mg/day of rifampicin rapidly relieved his symptoms and shortened the symptomatic period.
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Affiliation(s)
- Hiroyuki Suzuki
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Teruko Arinaga-Hino
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Tomoya Sano
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Yutaro Mihara
- Department of Pathology, Kurume University School of Medicine, Kurume, Japan
| | - Hironori Kusano
- Department of Pathology, Kurume University School of Medicine, Kurume, Japan
- Department of Diagnostic Pathology, National Hospital Organization Kokura Medical Center, Fukuoka, Japan
| | - Tatsuki Mizuochi
- Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Japan
| | - Takao Togawa
- Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Shogo Ito
- Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Tatsuya Ide
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Reiichiro Kuwahara
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Keisuke Amano
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Toshihiro Kawaguchi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Hirohisa Yano
- Department of Pathology, Kurume University School of Medicine, Kurume, Japan
| | - Masayoshi Kage
- Department of Medical Engineering, Junshin Gakuen University, Fukuoka, Japan
| | - Hironori Koga
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Takuji Torimura
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
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Dieudonné T, Herrera SA, Laursen MJ, Lejeune M, Stock C, Slimani K, Jaxel C, Lyons JA, Montigny C, Pomorski TG, Nissen P, Lenoir G. Autoinhibition and regulation by phosphoinositides of ATP8B1, a human lipid flippase associated with intrahepatic cholestatic disorders. eLife 2022; 11:75272. [PMID: 35416773 PMCID: PMC9045818 DOI: 10.7554/elife.75272] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 04/12/2022] [Indexed: 11/24/2022] Open
Abstract
P4-ATPases flip lipids from the exoplasmic to the cytosolic leaflet, thus maintaining lipid asymmetry in eukaryotic cell membranes. Mutations in several human P4-ATPase genes are associated with severe diseases, for example in ATP8B1 causing progressive familial intrahepatic cholestasis, a rare inherited disorder progressing toward liver failure. ATP8B1 forms a binary complex with CDC50A and displays a broad specificity to glycerophospholipids, but regulatory mechanisms are unknown. Here, we report functional studies and the cryo-EM structure of the human lipid flippase ATP8B1-CDC50A at 3.1 Å resolution. We find that ATP8B1 is autoinhibited by its N- and C-terminal tails, which form extensive interactions with the catalytic sites and flexible domain interfaces. Consistently, ATP hydrolysis is unleashed by truncation of the C-terminus, but also requires phosphoinositides, most markedly phosphatidylinositol-3,4,5-phosphate (PI(3,4,5)P3), and removal of both N- and C-termini results in full activation. Restored inhibition of ATP8B1 truncation constructs with a synthetic peptide mimicking the C-terminal segment further suggests molecular communication between N- and C-termini in the autoinhibition and demonstrates that the regulatory mechanism can be interfered with by exogenous compounds. A recurring (G/A)(Y/F)AFS motif of the C-terminal segment suggests that this mechanism is employed widely across P4-ATPase lipid flippases in plasma membrane and endomembranes.
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Affiliation(s)
- Thibaud Dieudonné
- Institute for Integrative Biology of the Cell, Université Paris-Saclay, CEA, CNRS, Gif-sur-Yvette, France
| | - Sara Abad Herrera
- Department of Molecular Biochemistry, Ruhr University Bochum, Bochum, Germany
| | | | - Maylis Lejeune
- Institute for Integrative Biology of the Cell, Université Paris-Saclay, CEA, CNRS, Gif-sur-Yvette, France
| | - Charlott Stock
- Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
| | - Kahina Slimani
- Institute for Integrative Biology of the Cell, Université Paris-Saclay, CEA, CNRS, Gif-sur-Yvette, France
| | - Christine Jaxel
- Institute for Integrative Biology of the Cell, Université Paris-Saclay, CEA, CNRS, Gif-sur-Yvette, France
| | - Joseph A Lyons
- Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
| | - Cédric Montigny
- Institute for Integrative Biology of the Cell, Université Paris-Saclay, CEA, CNRS, Gif-sur-Yvette, France
| | | | - Poul Nissen
- Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
| | - Guillaume Lenoir
- Institute for Integrative Biology of the Cell, Université Paris-Saclay, CEA, CNRS, Gif-sur-Yvette, France
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39
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Structural insights into the activation of autoinhibited human lipid flippase ATP8B1 upon substrate binding. Proc Natl Acad Sci U S A 2022; 119:e2118656119. [PMID: 35349344 PMCID: PMC9168909 DOI: 10.1073/pnas.2118656119] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
ATP8B1 is a P4 ATPase that maintains membrane asymmetry by transporting phospholipids across the cell membrane. Disturbance of lipid asymmetry will lead to the imbalance of the cell membrane and eventually, cell death. Thus, defects in ATP8B1 are usually associated with severe human diseases, such as intrahepatic cholestasis. The present structures of ATP8B1 complexed with its auxiliary noncatalytic partners CDC50A and CDC50B reveal an autoinhibited state of ATP8B1 that could be released upon substrate binding. Moreover, release of this autoinhibition could be facilitated by the bile acids, which are key factors that alter the membrane asymmetry of hepatocytes. This enabled us to figure out a feedback loop of bile acids and lipids across the cell membrane. The human P4 ATPase ATP8B1 in complex with the auxiliary noncatalytic protein CDC50A or CDC50B mediates the transport of cell-membrane lipids from the outer to the inner membrane leaflet, which is crucial to maintain the asymmetry of membrane lipids. Its dysfunction usually leads to an imbalance of bile-acid circulation and eventually causes intrahepatic cholestasis diseases. Here, we found that both ATP8B1–CDC50A and ATP8B1–CDC50B possess a higher ATPase activity in the presence of the most favored substrate phosphatidylserine (PS), and, moreover, that the PS-stimulated activity could be augmented upon the addition of bile acids. The 3.4-Å cryo-electron microscopy structures of ATP8B1–CDC50A and ATP8B1–CDC50B enabled us to capture a phosphorylated and autoinhibited state, with the N- and C-terminal tails separately inserted into the cytoplasmic interdomain clefts of ATP8B1. The PS-bound ATP8B1–CDC50A structure at 4.0-Å resolution indicated that the autoinhibited state could be released upon PS binding. Structural analysis combined with mutagenesis revealed the residues that determine the substrate specificity and a unique positively charged loop in the phosphorylated domain of ATP8B1 for the recruitment of bile acids. Together, we supplemented the Post–Albers transport cycle of P4 ATPases with an extra autoinhibited state of ATP8B1, which could be activated upon substrate binding. These findings not only provide structural insights into the ATP8B1-mediated restoration of human membrane lipid asymmetry during bile-acid circulation, but also advance our understanding of the molecular mechanism of P4 ATPases.
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40
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Pater JA, Penney C, O'Rielly DD, Griffin A, Kamal L, Brownstein Z, Vona B, Vinkler C, Shohat M, Barel O, French CR, Singh S, Werdyani S, Burt T, Abdelfatah N, Houston J, Doucette LP, Squires J, Glaser F, Roslin NM, Vincent D, Marquis P, Woodland G, Benoukraf T, Hawkey-Noble A, Avraham KB, Stanton SG, Young TL. Autosomal dominant non-syndromic hearing loss maps to DFNA33 (13q34) and co-segregates with splice and frameshift variants in ATP11A, a phospholipid flippase gene. Hum Genet 2022; 141:431-444. [PMID: 35278131 PMCID: PMC9035003 DOI: 10.1007/s00439-022-02444-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 02/22/2022] [Indexed: 11/20/2022]
Abstract
Sequencing exomes/genomes have been successful for identifying recessive genes; however, discovery of dominant genes including deafness genes (DFNA) remains challenging. We report a new DFNA gene, ATP11A, in a Newfoundland family with a variable form of bilateral sensorineural hearing loss (SNHL). Genome-wide SNP genotyping linked SNHL to DFNA33 (LOD = 4.77), a locus on 13q34 previously mapped in a German family with variable SNHL. Whole-genome sequencing identified 51 unremarkable positional variants on 13q34. Continuous clinical ascertainment identified several key recombination events and reduced the disease interval to 769 kb, excluding all but one variant. ATP11A (NC_000013.11: chr13:113534963G>A) is a novel variant predicted to be a cryptic donor splice site. RNA studies verified in silico predictions, revealing the retention of 153 bp of intron in the 3' UTR of several ATP11A isoforms. Two unresolved families from Israel were subsequently identified with a similar, variable form of SNHL and a novel duplication (NM_032189.3:c.3322_3327+2dupGTCCAGGT) in exon 28 of ATP11A extended exon 28 by 8 bp, leading to a frameshift and premature stop codon (p.Asn1110Valfs43Ter). ATP11A is a type of P4-ATPase that transports (flip) phospholipids from the outer to inner leaflet of cell membranes to maintain asymmetry. Haploinsufficiency of ATP11A, the phospholipid flippase that specially transports phosphatidylserine (PS) and phosphatidylethanolamine (PE), could leave cells with PS/PE at the extracellular side vulnerable to phagocytic degradation. Given that surface PS can be pharmaceutically targeted, hearing loss due to ATP11A could potentially be treated. It is also likely that ATP11A is the gene underlying DFNA33.
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Affiliation(s)
- Justin A Pater
- Faculty of Medicine, Memorial University, 300 Prince Phillip Drive, St. John's, NL, Canada
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Cindy Penney
- Faculty of Medicine, Memorial University, 300 Prince Phillip Drive, St. John's, NL, Canada
- Centre for Translational Genomics, Memorial University, 300 Prince Phillip Dr., St. John's, NL, Canada
| | - Darren D O'Rielly
- Faculty of Medicine, Memorial University, 300 Prince Phillip Drive, St. John's, NL, Canada
- Centre for Translational Genomics, Memorial University, 300 Prince Phillip Dr., St. John's, NL, Canada
| | - Anne Griffin
- Faculty of Medicine, Memorial University, 300 Prince Phillip Drive, St. John's, NL, Canada
| | - Lara Kamal
- Department of Human Molecular Genetics and Biochemistry, Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, 6997801, Tel Aviv, Israel
| | - Zippora Brownstein
- Department of Human Molecular Genetics and Biochemistry, Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, 6997801, Tel Aviv, Israel
| | - Barbara Vona
- Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany
- Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, Göttingen, Germany
| | - Chana Vinkler
- Institute of Medical Genetics, Wolfson Medical Center, 58100, Holon, Israel
| | - Mordechai Shohat
- Bioinformatic Center, Cancer Research Institute, The Wohl Institute for Translational Medicine, Sheba Medical Center, Tel-Hashomer, Israel
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ortal Barel
- Bioinformatic Center, Cancer Research Institute, The Wohl Institute for Translational Medicine, Sheba Medical Center, Tel-Hashomer, Israel
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Curtis R French
- Faculty of Medicine, Memorial University, 300 Prince Phillip Drive, St. John's, NL, Canada
| | - Sushma Singh
- Communication Sciences and Disorders, Elborn College, Western University, 1201 Western Road, London, ON, Canada
| | - Salem Werdyani
- Faculty of Medicine, Memorial University, 300 Prince Phillip Drive, St. John's, NL, Canada
| | - Taylor Burt
- Faculty of Medicine, Memorial University, 300 Prince Phillip Drive, St. John's, NL, Canada
| | - Nelly Abdelfatah
- Faculty of Medicine, Memorial University, 300 Prince Phillip Drive, St. John's, NL, Canada
| | - Jim Houston
- Faculty of Medicine, Memorial University, 300 Prince Phillip Drive, St. John's, NL, Canada
| | - Lance P Doucette
- Faculty of Medicine, Memorial University, 300 Prince Phillip Drive, St. John's, NL, Canada
| | - Jessica Squires
- Faculty of Medicine, Memorial University, 300 Prince Phillip Drive, St. John's, NL, Canada
| | - Fabian Glaser
- The Lorry I. Lokey Center for Life Sciences and Engineering, Technion-Israel Institute of Technology, Haifa, Israel
| | - Nicole M Roslin
- The Centre for Applied Genomics, The Hospital for Sick Children, Peter Gilgan Centre for Research and Learning, 686 Bay Street, Toronto, ON, Canada
| | - Daniel Vincent
- Genome Quebec Innovation Centre, McGill University, 740 Dr. Penfield Avenue, Montreal, QC, Canada
| | - Pascale Marquis
- Canadian Centre for Computational Genomics, McGill University and Genome Quebec Innovation Center, 740 Dr. Penfield Avenue, Montreal, QC, Canada
| | - Geoffrey Woodland
- Faculty of Medicine, Memorial University, 300 Prince Phillip Drive, St. John's, NL, Canada
| | - Touati Benoukraf
- Faculty of Medicine, Memorial University, 300 Prince Phillip Drive, St. John's, NL, Canada
| | - Alexia Hawkey-Noble
- Faculty of Medicine, Memorial University, 300 Prince Phillip Drive, St. John's, NL, Canada
| | - Karen B Avraham
- Department of Human Molecular Genetics and Biochemistry, Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, 6997801, Tel Aviv, Israel
| | - Susan G Stanton
- Communication Sciences and Disorders, Elborn College, Western University, 1201 Western Road, London, ON, Canada
| | - Terry-Lynn Young
- Faculty of Medicine, Memorial University, 300 Prince Phillip Drive, St. John's, NL, Canada.
- Centre for Translational Genomics, Memorial University, 300 Prince Phillip Dr., St. John's, NL, Canada.
- Communication Sciences and Disorders, Elborn College, Western University, 1201 Western Road, London, ON, Canada.
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Shankar S, Pande A, Geetha TS, Raichurkar K, Sakpal M, Lochan R, Asthana S. A New Variant of an Old Itch: Novel Missense Variant in ABCB4 Presenting with Intractable Pruritus. J Clin Exp Hepatol 2022; 12:701-704. [PMID: 35535055 PMCID: PMC9077154 DOI: 10.1016/j.jceh.2021.04.010] [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: 10/16/2020] [Accepted: 04/21/2021] [Indexed: 12/12/2022] Open
Abstract
We report a novel homozygous missense variant in ABCB4 gene in a Yemeni child born to consanguineous parents, with a significant family history of liver disease-related deaths, resulting in a progressive familial intrahepatic cholestasis (PFIC) type 3 phenotype requiring liver transplantation for intractable pruritus.
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Key Words
- ABCB11, ATP binding cassette subfamily B member 11
- ABCB4 mutation
- ABCB4, ATP-binding cassette subfamily B member 4
- ALT, Alanine aminotransferase
- AST, Aspartate aminotransferase
- ATP8B1, ATPase phospholipid transporting 8B1
- BSEP, bile salt export pump
- FXR, farnesoid X receptor
- GGT, Gamma Glutamyl- Transpeptidase
- ICP, Intrahepatic cholestasis of pregnancy
- MDR3, multidrug resistance p-glycoprotein 3
- MYO5B, Myosin 5B
- PFIC
- PFIC, Progressive familial intrahepatic cholestasis
- TJP2, Tight junction protein 2
- congenital liver disease
- liver transplantation
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Affiliation(s)
- Sahana Shankar
- Division of Pediatric Gastroenterology, Department of Pediatrics, Mazumdar Shaw Medical Centre, Narayana Health, Bangalore, India
| | - Apurva Pande
- Aster Integrated Liver Care, Aster CMI Hospital, Bangalore, India
| | - Thenral S. Geetha
- Medgenome Labs Pvt Ltd, 3rd Floor, Narayana Netralaya Building, # 258/A, Bommasandra, Hosur Road, Narayana Health City, Bangalore, 560 099, India
| | | | | | - Rajiv Lochan
- Aster Integrated Liver Care, Aster CMI Hospital, Bangalore, India
| | - Sonal Asthana
- Aster Integrated Liver Care, Aster CMI Hospital, Bangalore, India
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42
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Huang Y, Luo EP, Li M, Yang J, Gan JH, Zhao WF. Two novel ATP8B1 mutations involved in progressive familial intrahepatic cholestasis type 1 that is ameliorated by rifampicin: A case report. J Dig Dis 2022; 23:124-129. [PMID: 34985190 PMCID: PMC9304250 DOI: 10.1111/1751-2980.13078] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 11/17/2021] [Accepted: 12/31/2021] [Indexed: 12/11/2022]
Affiliation(s)
- Yan Huang
- Department of Infectious DiseasesFirst Affiliated Hospital of Soochow UniversitySuzhouJiangsu ProvinceChina
| | - Er Ping Luo
- Department of Infectious DiseasesFirst Affiliated Hospital of Soochow UniversitySuzhouJiangsu ProvinceChina
| | - Min Li
- Department of DermatologyFirst Affiliated Hospital of Soochow UniversitySuzhouJiangsu ProvinceChina
| | - Jing Yang
- Department of NephrologyFirst Affiliated Hospital of Soochow UniversitySuzhouJiangsu ProvinceChina
| | - Jian He Gan
- Department of Infectious DiseasesFirst Affiliated Hospital of Soochow UniversitySuzhouJiangsu ProvinceChina
| | - Wei Feng Zhao
- Department of Infectious DiseasesFirst Affiliated Hospital of Soochow UniversitySuzhouJiangsu ProvinceChina
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43
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Wang J, Yu C, Zhuang J, Qi W, Jiang J, Liu X, Zhao W, Cao Y, Wu H, Qi J, Zhao RC. The role of phosphatidylserine on the membrane in immunity and blood coagulation. Biomark Res 2022; 10:4. [PMID: 35033201 PMCID: PMC8760663 DOI: 10.1186/s40364-021-00346-0] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 11/01/2021] [Indexed: 12/17/2022] Open
Abstract
The negatively charged aminophospholipid, phosphatidylserine (PtdSer), is located in the inner leaflet of the plasma membrane in normal cells, and may be exposed to the outer leaflet under some immune and blood coagulation processes. Meanwhile, Ptdser exposed to apoptotic cells can be recognized and eliminated by various immune cells, whereas on the surface of activated platelets Ptdser interacts with coagulation factors prompting enhanced production of thrombin which significantly facilitates blood coagulation. In the case where PtdSer fails in exposure or mistakenly occurs, there are occurrences of certain immunological and haematological diseases, such as the Scott syndrome and Systemic lupus erythematosus. Besides, viruses (e.g., Human Immunodeficiency Virus (HIV), Ebola virus (EBOV)) can invade host cells through binding the exposed PtdSer. Most recently, the Corona Virus Disease 2019 (COVID-19) has been similarly linked to PtdSer or its receptors. Therefore, it is essential to comprehensively understand PtdSer and its functional characteristics. Therefore, this review summarizes Ptdser, its eversion mechanism; interaction mechanism, particularly with its immune receptors and coagulation factors; recognition sites; and its function in immune and blood processes. This review illustrates the potential aspects for the underlying pathogenic mechanism of PtdSer-related diseases, and the discovery of new therapeutic strategies as well.
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Affiliation(s)
- Jiao Wang
- School of Life Sciences, Shanghai University, 99 Shangda Road, Shanghai, 200444, China.
| | - Changxin Yu
- School of Life Sciences, Shanghai University, 99 Shangda Road, Shanghai, 200444, China
| | - Junyi Zhuang
- School of Life Sciences, Shanghai University, 99 Shangda Road, Shanghai, 200444, China
| | - Wenxin Qi
- School of Life Sciences, Shanghai University, 99 Shangda Road, Shanghai, 200444, China
| | - Jiawen Jiang
- School of Life Sciences, Shanghai University, 99 Shangda Road, Shanghai, 200444, China
| | - Xuanting Liu
- School of Life Sciences, Shanghai University, 99 Shangda Road, Shanghai, 200444, China
| | - Wanwei Zhao
- School of Life Sciences, Shanghai University, 99 Shangda Road, Shanghai, 200444, China
| | - Yiyang Cao
- School of Life Sciences, Shanghai University, 99 Shangda Road, Shanghai, 200444, China
| | - Hao Wu
- School of Life Sciences, Shanghai University, 99 Shangda Road, Shanghai, 200444, China
| | - Jingxuan Qi
- School of Life Sciences, Shanghai University, 99 Shangda Road, Shanghai, 200444, China
| | - Robert Chunhua Zhao
- School of Life Sciences, Shanghai University, 99 Shangda Road, Shanghai, 200444, China.
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, No. 5 Dongdansantiao, Beijing, 100005, China.
- Centre of Excellence in Tissue Engineering, Chinese Academy of Medical Sciences, Beijing, China.
- Beijing Key Laboratory of New Drug Development and Clinical Trial of Stem Cell Therapy (BZ0381), Beijing, China.
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44
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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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45
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Hasegawa J, Uchida Y, Mukai K, Lee S, Matsudaira T, Taguchi T. A Role of Phosphatidylserine in the Function of Recycling Endosomes. Front Cell Dev Biol 2022; 9:783857. [PMID: 35004683 PMCID: PMC8740049 DOI: 10.3389/fcell.2021.783857] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 11/29/2021] [Indexed: 11/13/2022] Open
Abstract
Cells internalize proteins and lipids in the plasma membrane (PM) and solutes in the extracellular space by endocytosis. The removal of PM by endocytosis is constantly balanced by the replenishment of proteins and lipids to PM through recycling pathway. Recycling endosomes (REs) are specific subsets of endosomes. Besides the established role of REs in recycling pathway, recent studies have revealed unanticipated roles of REs in membrane traffic and cell signalling. In this review, we highlight these emerging issues, with a particular focus on phosphatidylserine (PS), a phospholipid that is highly enriched in the cytosolic leaflet of RE membranes. We also discuss the pathogenesis of Hermansky Pudlak syndrome type 2 (HPS2) that arises from mutations in the AP3B1 gene, from the point of view of dysregulated RE functions.
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Affiliation(s)
- Junya Hasegawa
- Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan
| | - Yasunori Uchida
- Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan
| | - Kojiro Mukai
- Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan
| | - Shoken Lee
- Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan
| | - Tatsuyuki Matsudaira
- Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan
| | - Tomohiko Taguchi
- Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan
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46
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Advances in genetic, epigenetic and environmental aspects of rare liver diseases. Eur J Med Genet 2021; 65:104411. [PMID: 34942406 DOI: 10.1016/j.ejmg.2021.104411] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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47
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Henkel SAF, Salgado CM, Reyes-Mugica M, Soltys KA, Strauss K, Mazariegos GV, Squires RH, McKiernan PJ, Zhang X, Squires JE. Long-term liver transplant outcomes for progressive familial intrahepatic cholestasis type 1: The Pittsburgh experience. Pediatr Transplant 2021; 25:e14108. [PMID: 34339082 DOI: 10.1111/petr.14108] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 05/26/2021] [Accepted: 07/23/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND Progressive familial intrahepatic cholestasis type 1 (PFIC1) arises from biallelic variants in the ATP8B1 gene that annul FIC1 activity, resulting in progressive liver disease. Liver transplant (LT) is indicated in refractory disease; however, post-LT complications including worsening diarrhea and steatohepatitis progressing to fibrosis with graft loss have been reported. We aim to describe long-term outcomes of PFIC1 LT recipients at our center, focusing on the histological changes of the allografts. METHODS We assessed 7 PFIC1 patients post-LT at the Children's Hospital of Pittsburgh (CHP). All pre-transplant, explant, and sequential post-transplant pathology samples were reviewed. Continuous data are presented as the mean ± SD. We compared the pre- and post-transplant height and weight z-scores using Wilcoxon signed-rank test. RESULTS Seven (29% male) patients with PFIC1 received a LT (n = 6) or had post-LT care (n = 1) at CHP. Six had confirmed or suspected identical genetic. At a mean follow-up of 10.9 years, both patient survival and graft survival were 100%. Diarrhea persisted (n = 3) or newly developed (n = 4) in all patients after LT contributing to ongoing growth failure, with mean z-scores -2.63 (weight) and -2.98 (height) at follow-up. Histologically, allograft steatosis was common but was not accompanied by significant inflammation, ballooning, or fibrosis. CONCLUSION We show that extrahepatic disease persists and near-universal allograft steatosis occurs. However, at a mean follow-up period of over 10 years, no patients developed steatohepatitis or significant fibrosis, and both patient survival and graft survival are excellent.
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Affiliation(s)
- Sarah A F Henkel
- Department of Pediatric Gastroenterology and Hepatology, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Claudia M Salgado
- Department of Pathology, University of Pittsburgh, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Miguel Reyes-Mugica
- Department of Pathology, University of Pittsburgh, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Kyle A Soltys
- Hillman Center for Pediatric Transplantation, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Kevin Strauss
- Clinic for Special Children, Strasburg, PA, USA.,Department of Pediatrics, Penn Medicine-Lancaster General Hospital, Lancaster, PA, USA
| | - George V Mazariegos
- Hillman Center for Pediatric Transplantation, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Robert H Squires
- Department of Pediatric Gastroenterology and Hepatology, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Patrick J McKiernan
- Department of Pediatric Gastroenterology and Hepatology, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Xingyu Zhang
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - James E Squires
- Department of Pediatric Gastroenterology and Hepatology, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
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48
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Jeyaraj R, Bounford KM, Ruth N, Lloyd C, MacDonald F, Hendriksz CJ, Baumann U, Gissen P, Kelly D. The Genetics of Inherited Cholestatic Disorders in Neonates and Infants: Evolving Challenges. Genes (Basel) 2021; 12:1837. [PMID: 34828443 PMCID: PMC8621872 DOI: 10.3390/genes12111837] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 11/15/2021] [Accepted: 11/16/2021] [Indexed: 12/26/2022] Open
Abstract
Many inherited conditions cause cholestasis in the neonate or infant. Next-generation sequencing methods can facilitate a prompt diagnosis in some of these cases; application of these methods in patients with liver diseases of unknown cause has also uncovered novel gene-disease associations and improved our understanding of physiological bile secretion and flow. By helping to define the molecular basis of certain cholestatic disorders, these methods have also identified new targets for therapy as well patient subgroups more likely to benefit from specific therapies. At the same time, sequencing methods have presented new diagnostic challenges, such as the interpretation of single heterozygous genetic variants. This article discusses those challenges in the context of neonatal and infantile cholestasis, focusing on difficulties in predicting variant pathogenicity, the possibility of other causal variants not identified by the genetic screen used, and phenotypic variability among patients with variants in the same genes. A prospective, observational study performed between 2010-2013, which sequenced six important genes (ATP8B1, ABCB11, ABCB4, NPC1, NPC2 and SLC25A13) in an international cohort of 222 patients with infantile liver disease, is given as an example of potential benefits and challenges that clinicians could face having received a complex genetic result. Further studies including large cohorts of patients with paediatric liver disease are needed to clarify the spectrum of phenotypes associated with, as well as appropriate clinical response to, single heterozygous variants in cholestasis-associated genes.
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Affiliation(s)
- Rebecca Jeyaraj
- National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre, University College London, London WC1N 1EH, UK;
| | - Kirsten McKay Bounford
- West of Scotland Centre for Genomic Medicine, Queen Elizabeth University Hospital, Glasgow G51 4TF, UK;
| | - Nicola Ruth
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK; (N.R.); (U.B.); (D.K.)
- Liver Unit, Birmingham Women’s and Children’s Hospital, Birmingham B4 6NH, UK;
| | - Carla Lloyd
- Liver Unit, Birmingham Women’s and Children’s Hospital, Birmingham B4 6NH, UK;
| | - Fiona MacDonald
- West Midlands Regional Genetics Service, Birmingham Women’s and Children’s Hospital, Birmingham B15 2TG, UK;
| | - Christian J. Hendriksz
- Steve Biko Academic Unit, Level D3 New Pretoria Academic Hospital, Malherbe Street, Pretoria 0002, South Africa;
| | - Ulrich Baumann
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK; (N.R.); (U.B.); (D.K.)
- Paediatric Gastroenterology and Hepatology, Hannover Medical School, 30625 Hannover, Germany
| | - Paul Gissen
- National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre, University College London, London WC1N 1EH, UK
| | - Deirdre Kelly
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK; (N.R.); (U.B.); (D.K.)
- Liver Unit, Birmingham Women’s and Children’s Hospital, Birmingham B4 6NH, UK;
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49
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Yang Y, Zhang J, Li LT, Qiu YL, Gong JY, Zhang MH, Li CH, Wang JS. Whole-Genome Sequencing Reveals Large ATP8B1 Deletion/Duplications as Second Mutations Missed by Exome-Based Sequencing. J Mol Diagn 2021; 23:1491-1499. [PMID: 34543749 DOI: 10.1016/j.jmoldx.2021.07.028] [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: 02/28/2021] [Revised: 07/14/2021] [Accepted: 07/28/2021] [Indexed: 11/15/2022] Open
Abstract
Progressive familial intrahepatic cholestasis type 1 (PFIC1) results from biallelic pathogenic variants in ATP8B1. This study sought second pathogenic variants in ATP8B1 by whole-genome sequencing (WGS) in four unrelated low γ-glutamyl transpeptidase cholestasis patients in whom clinical suspicion of PFIC1 was high and gene-panel or Sanger sequencing had identified only one pathogenic variant in ATP8B1. Sanger sequencing confirmed WGS findings and determined the origin of each variant. Novel nonrecurrent structural variants in three patients (patient 1 to patient 3) were identified in trans: g.55396652_55403080del (6427-bp deletion), g.55335906_55346620dup (10,715-bp duplication), and g.55362063_55364293dup (2231-bp duplication). One synonymous variant in patient 4 was recognized in trans (c.1029G>A, p. Thr343Thr) and demonstrated as deleterious. In conclusion, WGS improves genetic diagnostic yield in PFIC1. These findings expand the gene-variant spectrum associated with familiar intrahepatic cholestasis 1 (FIC1) disease and for the first time report tandem duplication in ATP8B1 associated with cholestasis.
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Affiliation(s)
- Ye Yang
- The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China
| | - Jing Zhang
- The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China
| | - Li-Ting Li
- The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China
| | - Yi-Ling Qiu
- The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China; Department of Pediatrics, Jinshan Hospital, Fudan University, Shanghai, China
| | - Jing-Yu Gong
- Department of Pediatrics, Jinshan Hospital, Fudan University, Shanghai, China
| | - Mei-Hong Zhang
- Department of Pediatrics, Jinshan Hospital, Fudan University, Shanghai, China
| | - Cai-Hua Li
- Genesky Biotechnologies, Shanghai, China
| | - Jian-She Wang
- The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China.
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50
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Sun KX, Jiang XY, Li X, Su YJ, Wang JL, Zhang L, Yang YM, Zhu XJ. Deletion of phosphatidylserine flippase β-subunit Tmem30a in satellite cells leads to delayed skeletal muscle regeneration. Zool Res 2021; 42:650-659. [PMID: 34472226 PMCID: PMC8455468 DOI: 10.24272/j.issn.2095-8137.2021.195] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Abstract
Phosphatidylserine (PS) is distributed asymmetrically in the plasma membrane of eukaryotic cells. Phosphatidylserine flippase (P4-ATPase) transports PS from the outer leaflet of the lipid bilayer to the inner leaflet of the membrane to maintain PS asymmetry. The β subunit TMEM30A is indispensable for transport and proper function of P4-ATPase. Previous studies have shown that the ATP11A and TMEM30A complex is the molecular switch for myotube formation. However, the role of Tmem30a in skeletal muscle regeneration remains elusive. In the current study, Tmem30a was highly expressed in the tibialis anterior (TA) muscles of dystrophin-null (mdx) mice and BaCl2-induced muscle injury model mice. We generated a satellite cell (SC)-specific Tmem30a conditional knockout (cKO) mouse model to investigate the role of Tmem30a in skeletal muscle regeneration. The regenerative ability of cKO mice was evaluated by analyzing the number and diameter of regenerated SCs after the TA muscles were injured by BaCl2-injection. Compared to the control mice, the cKO mice showed decreased Pax7+ and MYH3+ SCs, indicating diminished SC proliferation, and decreased expression of muscular regulatory factors (MYOD and MYOG), suggesting impaired myoblast proliferation in skeletal muscle regeneration. Taken together, these results demonstrate the essential role of Tmem30a in skeletal muscle regeneration.
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Affiliation(s)
- Kuan-Xiang Sun
- Health Management Center, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China.,Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China.,Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072 China
| | - Xiao-Yan Jiang
- Health Management Center, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China.,Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China
| | - Xiao Li
- Health Management Center, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China.,Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China
| | - Yu-Jing Su
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China
| | - Ju-Lin Wang
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China
| | - Lin Zhang
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China
| | - Ye-Ming Yang
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China
| | - Xian-Jun Zhu
- Health Management Center, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China.,Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China.,Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072 China.,Department of Ophthalmology, First People's Hospital of Shangqiu, Shangqiu, Henan 476000, China.,Key Laboratory of Tibetan Medicine Research, Chinese Academy of Sciences and Qinghai Provincial Key Laboratory of Tibetan Medicine Research, Northwest Institute of Plateau Biology, Xining, Qinghai 810008, China. E-mail:
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