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Jiao J, Morotti R, Shafizadeh N, Jain D. Expanding the spectrum of progressive familial intrahepatic cholestasis: A report of 3 cases. Am J Clin Pathol 2025; 163:332-339. [PMID: 39333837 DOI: 10.1093/ajcp/aqae123] [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: 06/08/2024] [Accepted: 08/22/2024] [Indexed: 09/30/2024] Open
Abstract
OBJECTIVES Progressive familial intrahepatic cholestasis (PFIC) is a group of autosomal recessive disorders caused by defects in bile secretion or transport usually presenting as cholestasis in pediatric age. Herewith, we describe 3 PFIC cases with diagnostic challenges and highlight the role of genetic analysis. METHODS The clinical history, laboratory data, liver biopsy, and molecular analysis for each case were reviewed. RESULTS Case 1, a Hispanic male from Puerto Rico with hepatomegaly since age 2 months, was eventually diagnosed with PFIC3 following identification of a homozygous splice site variant in ATP binding cassette subfamily B member 4 (ABCB4) (c.2784-12T>C) at age 17 years by whole-exome sequencing (WES). Case 2 was a 37-year-old man with a history of alcoholism, abnormal liver function tests, and ductopenia on biopsy. Molecular testing revealed a pathogenic heterozygous ABCB4 mutation (c.1633C>T) variant leading to a diagnosis of PFIC3. Case 3 was a 2-year-old female initially presenting as a drug-induced liver injury but was diagnosed with PFIC10 following identification of a heterozygous frameshift mutation (p.Asp300Trpfs*19) and a heterozygous missense mutation (c.1357T>C) in myosin VB (MYO5B) by WES. CONCLUSIONS These PFIC cases highlight the heterogenous presentation and diagnostic challenges, and they emphasize the role of next-generation sequencing, particularly the utility of WES.
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Affiliation(s)
- Jingjing Jiao
- Department of Pathology, Yale School of Medicine, New Haven, CT, US
| | | | - Nafis Shafizadeh
- Department of Pathology, Southern California Permanente Medical Group, Woodland Hills Medical Center, Los Angeles, CA, US
| | - Dhanpat Jain
- Department of Pathology, Yale School of Medicine, New Haven, CT, US
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Qian ST, Chen LM, He MF, Li HJ. Zebrafish Larvae as a Predictive Model for the Risk of Chemical-Induced Cholestasis: Phenotypic Evaluation and Nomogram Formation. Chem Res Toxicol 2024; 37:1976-1988. [PMID: 39566033 DOI: 10.1021/acs.chemrestox.4c00324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2024]
Abstract
Chemical-induced cholestasis (CIC) has become a concern in chemical safety risk assessment in pharmaceutical, food, cosmetic, and industrial manufacturing. Currently, known animal and in vitro liver models are unsuitable as high-throughput screening tools due to their high cost, time-consuming, or poor screening accuracy. Herein, a cohort of chemicals validated as cholestatic hepatotoxic in humans, rodents, and in vitro liver models was established for testing. The accuracy and reliability of the detection of CIC in zebrafish larvae were assessed by liver phenotype, bile flow inhibition rate, bile acid distribution, biochemical indices, and RT-qPCR. In addition, the nomogram prediction model was constructed using binomial logistic regression analysis. The model was constructed with three variables: aspartate aminotransferase (AST.FC) level, total bile acid (TBA.FC) level, and fold change in the number of bile acid nodes per unit of bile ducts in the zebrafish liver (NPL.FC), which showed high predictive power (areas under the ROC curve: 0.983). Furthermore, this study demonstrated that zebrafish larvae have some model specificity for CIC risk assessment of estrogen endocrine disruptors and that testing after 10 dpf provides more scientific results. Overall, combining zebrafish larval phenotyping and nomograms is an efficient and powerful tool for CIC risk monitoring of chemicals.
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Affiliation(s)
- Si-Tong Qian
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, Jiangsu, China
| | - Liang-Min Chen
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, Jiangsu, China
| | - Ming-Fang He
- College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing 211816, Jiangsu, China
| | - Hui-Jun Li
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, Jiangsu, China
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3
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Wang S, Liu Q, Sun X, Wei W, Ding L, Zhao X. Identification of novel ABCB4 variants and genotype-phenotype correlation in progressive familial intrahepatic cholestasis type 3. Sci Rep 2024; 14:27381. [PMID: 39521930 PMCID: PMC11550383 DOI: 10.1038/s41598-024-79123-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Accepted: 11/06/2024] [Indexed: 11/16/2024] Open
Abstract
Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a severe hepatic disorder characterized by cholestasis. Elucidating the genotype-phenotype correlations and expanding the mutational spectrum of the ABCB4 gene are crucial for enhancing diagnostic accuracy and therapeutic strategies.Clinical and genetic data from 2 original PFIC3 patients from our institution, along with 118 additional cases identified through a comprehensive literature review, were integrated for a comprehensive analysis. The study included statistical analysis of clinical information, genetic analysis, multi-species sequence alignment, protein structure modeling, and pathogenicity assessment. Machine learning techniques were applied to identify genotype-phenotype relationships. We identified three novel ABCB4 mutations: two missense mutations (c.904G > T and c.2493G > C) and one splicing mutation (c.1230 + 1G > A). Homozygous mutations were associated with significantly earlier disease onset compared to compound heterozygous mutations (p < 0.0001). Missense mutations were predominant (76.9%), with Exon 7 being the most frequently affected region. A random forest model indicated that Exon 10 had the highest feature importance score (9.9%). Liver transplantation remains the most effective treatment modality for PFIC3. This investigation broadens the known mutation spectrum of the ABCB4 gene and identifies key variant sites associated with clinical manifestations. These insights lay a foundation for early diagnosis, optimal treatment selection, and further research into PFIC3.
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Affiliation(s)
- Senyan Wang
- Translational Medicine Centre, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450000, China
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Qi Liu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiaoyan Sun
- Department of Oncology, Henan Cancer Hospital, Zhengzhou University Affiliated Cancer Hospital, Zhengzhou, China
| | - Wenjuan Wei
- Translational Medicine Centre, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450000, China
| | - Leilei Ding
- Department of Obstetrics and Gynecology, Peking Union Medical College, National Clinical Research Center for Obstetric & Gynecologic Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, 100730, China.
| | - Xiaofang Zhao
- Translational Medicine Centre, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450000, China.
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Xu N, Gong L, Mi X, Yang W, Tang D. Magnetic resonance imaging features of progressive familial intrahepatic cholestasis type 3. RADIOLOGIE (HEIDELBERG, GERMANY) 2024; 64:102-108. [PMID: 38829428 DOI: 10.1007/s00117-024-01324-x] [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: 11/28/2023] [Accepted: 03/20/2024] [Indexed: 06/05/2024]
Abstract
PURPOSE Progressive familial intrahepatic cholestasis type 3 (PFIC-3) is a rare autosomal recessive cholestatic liver disorder. This study aimed to present the clinical and magnetic resonance imaging (MRI) features of three patients with PFIC‑3. METHODS The study included three patients with cholestasis and pathogenic variants in the ABCB4 gene identified by next-generation sequencing of a targeted-gene panel or by whole-exome sequencing. The clinical, laboratory, histological, molecular, and MRI features of the patients were collected. RESULTS Three patients (one male and two females) were enrolled. The age when clinical signs and symptoms were first noted was 21, 14, and 39 years, respectively, and the signs and symptoms included pruritus and splenomegaly (in all three patients). Parenchymatous lace-like fibrosis was associated with periportal hyperintensity and periportal halo sign in three patients. Segmental atrophy was observed in two patients, diffuse atrophy was observed in one patient, and liver surface irregularity caused by regenerating nodules was observed in three patients. Magnetic resonance cholangiopancreatography (MRCP) images showed irregular bile duct changes in three patients, focal hilar bile duct stenosis, and local intrahepatic bile duct dilatation. CONCLUSIONS Imaging studies using MRI and MRCP can support the clinical and laboratory results in cases of PFIC‑3 and can also be used as a noninvasive diagnostic option.
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Affiliation(s)
- Nina Xu
- Department of Medical Imaging (Radiology), the Affiliated Hospital of Hangzhou Normal University, Zhejiang, China
| | - Ling Gong
- Department of Infectious Disease (Liver Diseases), the Affiliated Hospital of Hangzhou Normal University, Zhejiang, China
| | - Xiaoxiao Mi
- Institute of Translational Medicine, the Affiliated Hospital of Hangzhou Normal University, Zhejiang, China
| | - Wenjun Yang
- Department of Pathology, the Affiliated Hospital of Hangzhou Normal University, Zhejiang, China
| | - Dong Tang
- Department of Medical Imaging (Radiology), the Affiliated Hospital of Hangzhou Normal University, Zhejiang, China.
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Li S, Hao L, Deng J, Zhang J, Yu F, Ye F, Li N, Hu X. The Culprit Behind HBV-Infected Hepatocytes: NTCP. Drug Des Devel Ther 2024; 18:4839-4858. [PMID: 39494152 PMCID: PMC11529284 DOI: 10.2147/dddt.s480151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Accepted: 10/16/2024] [Indexed: 11/05/2024] Open
Abstract
Hepatitis B virus (HBV) is a globally prevalent human DNA virus responsible for over 250 million cases of chronic liver infections, leading to conditions such as liver inflammation, cirrhosis and hepatocellular carcinoma (HCC). Sodium taurocholate co-transporting polypeptide (NTCP) is a transmembrane protein highly expressed in human hepatocytes and functions as a bile acid (BA) transporter. NTCP has been identified as the receptor that HBV and its satellite virus, hepatitis delta virus (HDV), use to enter hepatocytes. HBV entry into hepatocytes is tightly regulated by various signaling pathways, and NTCP plays an important role as the initial stage of HBV infection. NTCP acts as an initiation signal, causing metabolic changes in hepatocytes and facilitating the entry of HBV into hepatocytes. Thus, a comprehensive understanding of NTCP's role is crucial. In this review, we will examine the regulatory mechanisms governing HBV pre-S1 binding to liver membrane NTCP, the role of NTCP in HBV internalization, and the transcriptional and translational regulation of NTCP expression. Additionally, we will discuss clinical drugs targeting NTCP, including combination therapies involving NTCP inhibitors, and consider the safety of NTCP as a therapeutic target.
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Affiliation(s)
- Shenghao Li
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, People’s Republic of China
- Department of Infectious Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, People’s Republic of China
| | - Liyuan Hao
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, People’s Republic of China
- Department of Infectious Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, People’s Republic of China
| | - Jiali Deng
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, People’s Republic of China
- Department of Infectious Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, People’s Republic of China
| | - Junli Zhang
- Department of Infectious Diseases, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu Province, People’s Republic of China
| | - Fei Yu
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, People’s Republic of China
- Department of Infectious Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, People’s Republic of China
| | - Fanghang Ye
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, People’s Republic of China
- Department of Infectious Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, People’s Republic of China
| | - Na Li
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, People’s Republic of China
- Department of Infectious Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, People’s Republic of China
| | - Xiaoyu Hu
- Department of Infectious Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, People’s Republic of China
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Guan G, Cao H, Tang Z, Zhang K, Zhong M, Lv R, Wan W, Guo F, Wang Y, Gao Y. Mechanistic studies on the alleviation of ANIT-induced cholestatic liver injury by Polygala fallax Hemsl. polysaccharides. JOURNAL OF ETHNOPHARMACOLOGY 2024; 328:118108. [PMID: 38574780 DOI: 10.1016/j.jep.2024.118108] [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: 11/20/2023] [Revised: 03/09/2024] [Accepted: 03/23/2024] [Indexed: 04/06/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Polygala fallax Hemsl. is a traditional folk medicine commonly used by ethnic minorities in the Guangxi Zhuang Autonomous Region, and has a traditional application in the treatment of liver disease. Polygala fallax Hemsl. polysaccharides (PFPs) are of interest for their potential health benefits. AIM OF THIS STUDY This study explored the impact of PFPs on a mouse model of cholestatic liver injury (CLI) induced by alpha-naphthyl isothiocyanate (ANIT), as well as the potential mechanisms. MATERIALS AND METHODS A mouse CLI model was constructed using ANIT (80 mg/kg) and intervened with different doses of PFPs or ursodeoxycholic acid. Their serum biochemical indices, hepatic oxidative stress indices, and hepatic pathological characteristics were investigated. Then RNA sequencing was performed on liver tissues to identify differentially expressed genes and signaling pathways and to elucidate the mechanism of liver protection by PFPs. Finally, Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were used to verify the differentially expressed genes. RESULTS Data analyses showed that PFPs reduced the levels of liver function-related biochemical indices, such as ALT, AST, AKP, TBA, DBIL, and TBIL. PFPs up-regulated the activities of SOD and GSH, down-regulated the contents of MDA, inhibited the release of IL-1β, IL-6, and TNF-α, or promoted IL-10. Pathologic characterization of the liver revealed that PFPs reduced hepatocyte apoptosis or necrosis. The RNA sequencing indicated that the genes with differential expression were primarily enriched for the biosynthesis of primary bile acids, secretion or transportation of bile, the reactive oxygen species in chemical carcinogenesis, and the NF-kappa B signaling pathway. In addition, the results of qRT-PCR and Western blotting analysis were consistent with those of RNA sequencing analysis. CONCLUSIONS In summary, this study showed that PFPs improved intrahepatic cholestasis and alleviated liver damage through the modulation of primary bile acid production, Control of protein expression related to bile secretion or transportation, decrease in inflammatory reactions, and inhibition of oxidative pressure. As a result, PFPs might offer a hopeful ethnic dietary approach for managing intrahepatic cholestasis.
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Affiliation(s)
- Guoqiang Guan
- Department of Anesthesiology, Affiliated Hospital of Guilin Medical University, Guilin, 541001, China; Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, Guilin, 541199, China
| | - Houkang Cao
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, Guilin, 541199, China
| | - Zixuan Tang
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, Guilin, 541199, China
| | - Kefeng Zhang
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, Guilin, 541199, China
| | - Mingli Zhong
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, Guilin, 541199, China
| | - Rui Lv
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, Guilin, 541199, China
| | - Weimin Wan
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, Guilin, 541199, China
| | - Fengyue Guo
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, Guilin, 541199, China
| | - Yongwang Wang
- Department of Anesthesiology, Affiliated Hospital of Guilin Medical University, Guilin, 541001, China.
| | - Ya Gao
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, Guilin, 541199, China.
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Joshi D, Nayagam J, Clay L, Yerlett J, Claridge L, Day J, Ferguson J, Mckie P, Vara R, Pargeter H, Lockyer R, Jones R, Heneghan M, Samyn M. UK guideline on the transition and management of childhood liver diseases in adulthood. Aliment Pharmacol Ther 2024; 59:812-842. [PMID: 38385884 DOI: 10.1111/apt.17904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 10/15/2023] [Accepted: 02/03/2024] [Indexed: 02/23/2024]
Abstract
INTRODUCTION Improved outcomes of liver disease in childhood and young adulthood have resulted in an increasing number of young adults (YA) entering adult liver services. The adult hepatologist therefore requires a working knowledge in diseases that arise almost exclusively in children and their complications in adulthood. AIMS To provide adult hepatologists with succinct guidelines on aspects of transitional care in YA relevant to key disease aetiologies encountered in clinical practice. METHODS A systematic literature search was undertaken using the Pubmed, Medline, Web of Knowledge and Cochrane database from 1980 to 2023. MeSH search terms relating to liver diseases ('cholestatic liver diseases', 'biliary atresia', 'metabolic', 'paediatric liver diseases', 'autoimmune liver diseases'), transition to adult care ('transition services', 'young adult services') and adolescent care were used. The quality of evidence and the grading of recommendations were appraised using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. RESULTS These guidelines deal with the transition of YA and address key aetiologies for the adult hepatologist under the following headings: (1) Models and provision of care; (2) screening and management of mental health disorders; (3) aetiologies; (4) timing and role of liver transplantation; and (5) sexual health and fertility. CONCLUSIONS These are the first nationally developed guidelines on the transition and management of childhood liver diseases in adulthood. They provide a framework upon which to base clinical care, which we envisage will lead to improved outcomes for YA with chronic liver disease.
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Affiliation(s)
- Deepak Joshi
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, UK
| | - Jeremy Nayagam
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, UK
| | - Lisa Clay
- Paediatric Liver, GI and Nutrition service, King's College Hospital NHS Foundation Trust, London, UK
| | - Jenny Yerlett
- Paediatric Liver, GI and Nutrition service, King's College Hospital NHS Foundation Trust, London, UK
| | - Lee Claridge
- Leeds Liver Unit, St James's University Hospital, Leeds, UK
| | - Jemma Day
- Department of Psychology, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | - James Ferguson
- National Institute for Health Research, Birmingham Biomedical Research Centre, University of Birmingham, Birmingham, UK
| | - Paul Mckie
- Department of Social Work, King's College Hospital NHS Foundation Trust, London, UK
| | - Roshni Vara
- Paediatric Liver, GI and Nutrition service, King's College Hospital NHS Foundation Trust, London, UK
- Evelina London Children's Hospital, London, UK
| | | | | | - Rebecca Jones
- Leeds Liver Unit, St James's University Hospital, Leeds, UK
| | - Michael Heneghan
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, UK
| | - Marianne Samyn
- Paediatric Liver, GI and Nutrition service, King's College Hospital NHS Foundation Trust, London, UK
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Xiang D, Yang J, Liu L, Yu H, Gong X, Liu D. The regulation of tissue-specific farnesoid X receptor on genes and diseases involved in bile acid homeostasis. Biomed Pharmacother 2023; 168:115606. [PMID: 37812893 DOI: 10.1016/j.biopha.2023.115606] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2023] [Revised: 09/23/2023] [Accepted: 09/26/2023] [Indexed: 10/11/2023] Open
Abstract
Bile acids (BAs) facilitate the absorption of dietary lipids and vitamins and have also been identified as signaling molecules involved in regulating their own metabolism, glucose and lipid metabolism, as well as immunity. Disturbances in BA homeostasis are associated with various enterohepatic and metabolic diseases, such as cholestasis, nonalcoholic steatohepatitis, inflammatory bowel disease, and obesity. As a key regulator, the nuclear orphan receptor farnesoid X receptor (FXR, NR1H4) precisely regulates BA homeostasis by transcriptional regulation of genes involved in BA synthesis, metabolism, and enterohepatic circulation. FXR is widely regarded as the most potential therapeutic target. Obeticholic acid is the only FXR agonist approved to treat patients with primary biliary cholangitis, but its non-specific activation of systemic FXR also causes high-frequency side effects. In recent years, developing tissue-specific FXR-targeting drugs has become a research highlight. This article provides a comprehensive overview of the role of tissue-specific intestine/liver FXR in regulating genes involved in BA homeostasis and briefly discusses tissue-specific FXR as a therapeutic target for treating diseases. These findings provide the basis for the development of tissue-specific FXR modulators for the treatment of enterohepatic and metabolic diseases associated with BA dysfunction.
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Affiliation(s)
- Dong Xiang
- Department of Pharmacy, Tongji Hospital Affiliated with Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
| | - Jinyu Yang
- Department of Pharmacy, Tongji Hospital Affiliated with Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Lu Liu
- Department of Pharmacy, Tongji Hospital Affiliated with Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Hengyi Yu
- Department of Pharmacy, Tongji Hospital Affiliated with Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xuepeng Gong
- Department of Pharmacy, Tongji Hospital Affiliated with Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
| | - Dong Liu
- Department of Pharmacy, Tongji Hospital Affiliated with Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
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Liu H, Irobalieva RN, Kowal J, Ni D, Nosol K, Bang-Sørensen R, Lancien L, Stahlberg H, Stieger B, Locher KP. Structural basis of bile salt extrusion and small-molecule inhibition in human BSEP. Nat Commun 2023; 14:7296. [PMID: 37949847 PMCID: PMC10638440 DOI: 10.1038/s41467-023-43109-1] [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] [Received: 07/19/2023] [Accepted: 10/31/2023] [Indexed: 11/12/2023] Open
Abstract
BSEP (ABCB11) is an ATP-binding cassette transporter that is expressed in hepatocytes and extrudes bile salts into the canaliculi of the liver. BSEP dysfunction, caused by mutations or induced by drugs, is frequently associated with severe cholestatic liver disease. We report the cryo-EM structure of glibenclamide-bound human BSEP in nanodiscs, revealing the basis of small-molecule inhibition. Glibenclamide binds the apex of a central binding pocket between the transmembrane domains, preventing BSEP from undergoing conformational changes, and thus rationalizing the reduced uptake of bile salts. We further report two high-resolution structures of BSEP trapped in distinct nucleotide-bound states by using a catalytically inactivated BSEP variant (BSEPE1244Q) to visualize a pre-hydrolysis state, and wild-type BSEP trapped by vanadate to visualize a post-hydrolysis state. Our studies provide structural and functional insight into the mechanism of bile salt extrusion and into small-molecule inhibition of BSEP, which may rationalize drug-induced liver toxicity.
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Affiliation(s)
- Hongtao Liu
- Institute of Molecular Biology and Biophysics, ETH Zürich, Zürich, Switzerland
| | | | - Julia Kowal
- Institute of Molecular Biology and Biophysics, ETH Zürich, Zürich, Switzerland
| | - Dongchun Ni
- Laboratory of Biological Electron Microscopy, Institute of Physics, School of Basic Science, EPFL, and Department of Fundamental Microbiology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
| | - Kamil Nosol
- Institute of Molecular Biology and Biophysics, ETH Zürich, Zürich, Switzerland
| | - Rose Bang-Sørensen
- Institute of Molecular Biology and Biophysics, ETH Zürich, Zürich, Switzerland
| | - Loïck Lancien
- Institute of Molecular Biology and Biophysics, ETH Zürich, Zürich, Switzerland
| | - Henning Stahlberg
- Laboratory of Biological Electron Microscopy, Institute of Physics, School of Basic Science, EPFL, and Department of Fundamental Microbiology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
| | - Bruno Stieger
- Institute of Molecular Biology and Biophysics, ETH Zürich, Zürich, Switzerland
| | - Kaspar P Locher
- Institute of Molecular Biology and Biophysics, ETH Zürich, Zürich, Switzerland.
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10
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Li T, Yang C, Cao H, Mo S, Li B, Huang Z, Zhang R, Wu J, Zhang K, Gao Y. The Effect of Bergenin on Isonicotinic Acid Hydrazide and Rifampicin-Induced Liver Injury Revealed by RNA Sequencing. Molecules 2023; 28:5496. [PMID: 37513369 PMCID: PMC10386747 DOI: 10.3390/molecules28145496] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 06/29/2023] [Accepted: 07/17/2023] [Indexed: 07/30/2023] Open
Abstract
Bergenin (BER), a natural component of polyphenols, has a variety of pharmacological activities, especially in improving drug metabolism, reducing cholestasis, anti-oxidative stress and inhibiting inflammatory responses. The aim of this study was to investigate the effects of BER on liver injury induced by isonicotinic acid hydrazide (INH) and rifampicin (RIF) in mice. The mice model of liver injury was established with INH (100 mg/kg)+RIF (100 mg/kg), and then different doses of BER were used to intervene. The pathological morphology and biochemical indicators of mice were detected. Meanwhile, RNA sequencing was performed to screen the differentially expressed genes and signaling pathways. Finally, critical differentially expressed genes were verified by qRT-PCR and Western blot. RNA sequencing results showed that 707 genes were significantly changed in the INH+RIF group compared with the Control group, and 496 genes were significantly changed after the BER intervention. These differentially expressed genes were mainly enriched in the drug metabolism, bile acid metabolism, Nrf2 pathway and TLR4 pathway. The validation results of qRT-PCR and Western blot were consistent with the RNA sequencing. Therefore, BER alleviated INH+RIF-induced liver injury in mice. The mechanism of BER improving INH+RIF-induced liver injury was related to regulating drug metabolism enzymes, bile acid metabolism, Nrf2 pathway and TLR4 pathway.
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Affiliation(s)
- Ting Li
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, Guilin 541199, China
- Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin 541199, China
| | - Chaoyue Yang
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, Guilin 541199, China
- Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin 541199, China
| | - Houkang Cao
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, Guilin 541199, China
- Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin 541199, China
| | - Siyi Mo
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, Guilin 541199, China
- Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin 541199, China
| | - Bo Li
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, Guilin 541199, China
- Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin 541199, China
| | - Zhipeng Huang
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, Guilin 541199, China
- Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin 541199, China
| | - Ruobing Zhang
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, Guilin 541199, China
- Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin 541199, China
| | - Jianzhao Wu
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, Guilin 541199, China
- Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin 541199, China
| | - Kefeng Zhang
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, Guilin 541199, China
- Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin 541199, China
| | - Ya Gao
- Pharmacology Laboratory of Prevention and Treatment of High Incidence of Disease, Guilin Medical University, Guilin 541199, China
- Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin 541199, China
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Pan Q, Zhu G, Xu Z, Zhu J, Ouyang J, Tong Y, Zhao N, Zhang X, Cheng Y, Zhang L, Tan Y, Li J, Zhang C, Chen W, Cai SY, Boyer JL, Chai J. Organic Anion Transporting Polypeptide (OATP) 1B3 is a Significant Transporter for Hepatic Uptake of Conjugated Bile Acids in Humans. Cell Mol Gastroenterol Hepatol 2023; 16:223-242. [PMID: 37146714 PMCID: PMC10394288 DOI: 10.1016/j.jcmgh.2023.04.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 04/18/2023] [Accepted: 04/18/2023] [Indexed: 05/07/2023]
Abstract
BACKGROUND & AIMS OATP1B3/SLCO1B3 is a human liver-specific transporter for the clearance of endogenous compounds (eg, bile acid [BA]) and xenobiotics. The functional role of OATP1B3 in humans has not been characterized, as SLCO1B3 is poorly conserved among species without mouse orthologs. METHODS Slc10a1-knockout (Slc10a1-/-), Slc10a1hSLCO1B3 (endogenous mouse Slc10a1 promoter-driven human-SLCO1B3 expression in Slc10a1-/- mice), and human SLCO1B3 liver-specific transgenic (hSLCO1B3-LTG) mice were generated and challenged with 0.1% ursodeoxycholic-acid (UDCA), 1% cholic-acid (CA) diet, or bile duct ligation (BDL) for functional studies. Primary hepatocytes and hepatoma-PLC/RPF/5 cells were used for mechanistic studies. RESULTS Serum BA levels in Slc10a1-/- mice were substantially increased with or without 0.1% UDCA feeding compared with wild-type (WT) mice. This increase was attenuated in Slc10a1hSLCO1B3-mice, indicating that OATP1B3 functions as a significant hepatic BA uptake transporter. In vitro assay using primary hepatocytes from WT, Slc10a1-/-, and Slc10a1hSLCO1B3-mice indicated that OATP1B3 has a similar capacity in taking up taurocholate/TCA as Ntcp. Furthermore, TCA-induced bile flow was significantly impaired in Slc10a1-/- mice but partially recovered in Slc10a1hSLC01B3-mice, indicating that OATP1B3 can partially compensate the NTCP function in vivo. Liver-specific overexpression of OATP1B3 markedly increased the level of hepatic conjugated BA and cholestatic liver injury in 1% CA-fed and BDL mice. Mechanistic studies revealed that conjugated BAs stimulated Ccl2 and Cxcl2 in hepatocytes to increase hepatic neutrophil infiltration and proinflammatory cytokine production (eg, IL-6), which activated STAT3 to repress OATP1B3 expression by binding to its promoter. CONCLUSIONS Human OATP1B3 is a significant BA uptake transporter and can partially compensate Ntcp for conjugated BA uptake in mice. Its downregulation in cholestasis is an adaptive protective response.
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Affiliation(s)
- Qiong Pan
- Department of Gastroenterology, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, China; Insitute of Digestive Diseases of PLA, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, China; Center for Cholestatic Liver Diseases and Center for Metabolic Associated Fatty Liver Disease, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, China
| | - Guanyu Zhu
- Department of Gastroenterology, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, China; Insitute of Digestive Diseases of PLA, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, China; Center for Cholestatic Liver Diseases and Center for Metabolic Associated Fatty Liver Disease, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, China
| | - Ziqian Xu
- Department of Gastroenterology, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, China; Insitute of Digestive Diseases of PLA, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, China; Center for Cholestatic Liver Diseases and Center for Metabolic Associated Fatty Liver Disease, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, China
| | - Jinfei Zhu
- Department of Gastroenterology, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, China; Insitute of Digestive Diseases of PLA, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, China; Center for Cholestatic Liver Diseases and Center for Metabolic Associated Fatty Liver Disease, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, China; Queen Mary School, Nanchang University, Nanchang, Jiangxi, China
| | - Jiafeng Ouyang
- Department of Gastroenterology, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, China; Insitute of Digestive Diseases of PLA, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, China; Center for Cholestatic Liver Diseases and Center for Metabolic Associated Fatty Liver Disease, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, China
| | - Yao Tong
- Department of Gastroenterology, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, China; Insitute of Digestive Diseases of PLA, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, China; Center for Cholestatic Liver Diseases and Center for Metabolic Associated Fatty Liver Disease, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, China
| | - Nan Zhao
- Department of Gastroenterology, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, China; Insitute of Digestive Diseases of PLA, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, China; Center for Cholestatic Liver Diseases and Center for Metabolic Associated Fatty Liver Disease, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, China
| | - Xiaoxun Zhang
- Department of Gastroenterology, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, China; Insitute of Digestive Diseases of PLA, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, China; Center for Cholestatic Liver Diseases and Center for Metabolic Associated Fatty Liver Disease, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, China
| | - Ying Cheng
- Department of Gastroenterology, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, China; Insitute of Digestive Diseases of PLA, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, China; Center for Cholestatic Liver Diseases and Center for Metabolic Associated Fatty Liver Disease, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, China
| | - Liangjun Zhang
- Department of Gastroenterology, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, China; Insitute of Digestive Diseases of PLA, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, China; Center for Cholestatic Liver Diseases and Center for Metabolic Associated Fatty Liver Disease, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, China
| | - Ya Tan
- Department of Gastroenterology, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, China; Insitute of Digestive Diseases of PLA, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, China; Center for Cholestatic Liver Diseases and Center for Metabolic Associated Fatty Liver Disease, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, China
| | - Jianwei Li
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Chengcheng Zhang
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Wensheng Chen
- Department of Gastroenterology, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, China; Insitute of Digestive Diseases of PLA, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, China; Center for Cholestatic Liver Diseases and Center for Metabolic Associated Fatty Liver Disease, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, China
| | - Shi-Ying Cai
- Department of Internal Medicine and Liver Center, Yale University School of Medicine, New Haven, Connecticut
| | - James L Boyer
- Department of Internal Medicine and Liver Center, Yale University School of Medicine, New Haven, Connecticut
| | - Jin Chai
- Department of Gastroenterology, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, China; Insitute of Digestive Diseases of PLA, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, China; Center for Cholestatic Liver Diseases and Center for Metabolic Associated Fatty Liver Disease, the First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, China.
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Özvegy-Laczka C, Ungvári O, Bakos É. Fluorescence-based methods for studying activity and drug-drug interactions of hepatic solute carrier and ATP binding cassette proteins involved in ADME-Tox. Biochem Pharmacol 2023; 209:115448. [PMID: 36758706 DOI: 10.1016/j.bcp.2023.115448] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 01/31/2023] [Accepted: 02/01/2023] [Indexed: 02/11/2023]
Abstract
In humans, approximately 70% of drugs are eliminated through the liver. This process is governed by the concerted action of membrane transporters and metabolic enzymes. Transporters mediating hepatocellular uptake of drugs belong to the SLC (Solute carrier) superfamily of transporters. Drug efflux either toward the portal vein or into the bile is mainly mediated by active transporters of the ABC (ATP Binding Cassette) family. Alteration in the function and/or expression of liver transporters due to mutations, disease conditions, or co-administration of drugs or food components can result in altered pharmacokinetics. On the other hand, drugs or food components interacting with liver transporters may also interfere with liver function (e.g., bile acid homeostasis) and may even cause liver toxicity. Accordingly, certain transporters of the liver should be investigated already at an early stage of drug development. Most frequently radioactive probes are applied in these drug-transporter interaction tests. However, fluorescent probes are cost-effective and sensitive alternatives to radioligands, and are gaining wider application in drug-transporter interaction tests. In our review, we summarize our current understanding about hepatocyte ABC and SLC transporters affected by drug interactions. We provide an update of the available fluorescent and fluorogenic/activable probes applicable in in vitro or in vivo testing of these ABC and SLC transporters, including near-infrared transporter probes especially suitable for in vivo imaging. Furthermore, our review gives a comprehensive overview of the available fluorescence-based methods, not directly relying on the transport of the probe, suitable for the investigation of hepatic ABC or SLC-type drug transporters.
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Affiliation(s)
- Csilla Özvegy-Laczka
- Institute of Enzymology, RCNS, Eötvös Loránd Research Network, H-1117 Budapest, Magyar tudósok krt. 2., Hungary.
| | - Orsolya Ungvári
- Institute of Enzymology, RCNS, Eötvös Loránd Research Network, H-1117 Budapest, Magyar tudósok krt. 2., Hungary; Doctoral School of Biology, Institute of Biology, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Éva Bakos
- Institute of Enzymology, RCNS, Eötvös Loránd Research Network, H-1117 Budapest, Magyar tudósok krt. 2., Hungary
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Jiang JL, Liu X, Pan ZQ, Jiang XL, Shi JH, Chen Y, Yi Y, Zhong WW, Liu KY, He YH. Postoperative jaundice related to UGT1A1 and ABCB11 gene mutations: A case report and literature review. World J Clin Cases 2023; 11:1393-1402. [PMID: 36926131 PMCID: PMC10013108 DOI: 10.12998/wjcc.v11.i6.1393] [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: 11/08/2022] [Revised: 12/07/2022] [Accepted: 02/02/2023] [Indexed: 02/23/2023] Open
Abstract
BACKGROUND Patients with obstructive jaundice caused by intrahepatic bile duct stones can be effectively managed by surgery. However, some patients may develop postoperative complications, liver failure, and other life-threatening situations. Here, we report a patient with mutations in the uridine 5'-diphospho-glucuronosyltransferase 1A1 (UGT1A1) and bile salt export pump (adenosine triphosphate-binding cassette subfamily B member 11, ABCB11) genes who presented multiple intrahepatic bile duct stones and cholestasis, and the jaundice of the patient increased after partial hepatectomy. CASE SUMMARY A 52-year-old male patient admitted to the hospital on October 23, 2021, with a progressive exacerbation of jaundice, was found to have multiple intrahepatic bile duct stones with the diagnoses of obstructive jaundice and acute cholecystitis. Subsequently, the patient underwent left hepatectomy with biliary exploration, stone extraction, T-tube drainage, and cholecystectomy without developing any intraoperative complications. The patient had a dark urine color with worsening jaundice postoperatively and did not respond well to plasma exchange and other symptomatic and supportive treatments. Since the progressive increase in postoperative bilirubin could not be clinically explained with any potential reason, including, if not at all, viral infection, cholangitis, autoimmune liver disease, and other causes, the patient underwent whole-exon screening for any genetic diseases, which surprisingly identified UGT1A1 and ABCB11 gene mutations related to glucuronidation of indirect bilirubin as well as bile acid transport in hepatocytes, respectively. Thus, we hypothesized that postoperative refractory cholestasis might result from UGT1A1 and ABCB11 gene mutations and further recommended liver transplantation to the patient, who eventually declined it and died from liver failure six months later. CONCLUSION Surgery may aggravate cholestasis in patients with multiple intrahepatic bile duct stones and cholestasis associated with UGT1A1 and ABCB11 gene mutations. A liver transplant may be the best option if active medical treatment fails.
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Affiliation(s)
- Jin-Lian Jiang
- Department of Infectious Diseases, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Xia Liu
- Department of Infectious Diseases, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Zhong-Qin Pan
- Department of Infectious Diseases, People's Hospital Qiandongnan Miao and Dong Autonomous Prefecture, Kaili 556000, Guizhou Province, China
| | - Xiao-Ling Jiang
- Department of Infectious Diseases, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Jun-Hua Shi
- Department of Radiology, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Ya Chen
- Department of Infectious Diseases, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Yu Yi
- Department of Infectious Diseases, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Wei-Wei Zhong
- Department of Gastroenterology, First People’s Hospital of Jinmen, Jinmen 448000, Hubei Province, China
| | - Kang-Yan Liu
- Department of Infectious Diseases, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Yi-Huai He
- Department of Infectious Diseases, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
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Stindt J, Dröge C, Lainka E, Kathemann S, Pfister ED, Baumann U, Stalke A, Grabhorn E, Shagrani MA, Mozer-Glassberg Y, Hartley J, Wammers M, Klindt C, Philippski P, Liebe R, Herebian D, Mayatepek E, Berg T, Schmidt-Choudhury A, Wiek C, Hanenberg H, Luedde T, Keitel V. Cell-based BSEP trans-inhibition: A novel, non-invasive test for diagnosis of antibody-induced BSEP deficiency. JHEP Rep 2023. [DOI: 10.1016/j.jhepr.2023.100690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
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15
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Cristina Igreja Sá I, Tripska K, Alaei Faradonbeh F, Hroch M, Lastuvkova H, Schreiberova J, Kacerovsky M, Pericacho M, Nachtigal P, Micuda S. Labetalol and soluble endoglin aggravate bile acid retention in mice with ethinylestradiol-induced cholestasis. Front Pharmacol 2023; 14:1116422. [PMID: 36778021 PMCID: PMC9909014 DOI: 10.3389/fphar.2023.1116422] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 01/16/2023] [Indexed: 01/27/2023] Open
Abstract
Labetalol is used for the therapy of hypertension in preeclampsia. Preeclampsia is characterized by high soluble endoglin (sEng) concentration in plasma and coincides with intrahepatic cholestasis during pregnancy (ICP), which threatens the fetus with the toxicity of cumulating bile acids (BA). Therefore, we hypothesized that both labetalol and increased sEng levels worsen BA cumulation in estrogen-induced cholestasis. C57BL/6J, transgenic mice overexpressing human sEng, and their wild-type littermates were administrated with ethinylestradiol (EE, 10 mg/kg s.c., the mice model of ICP) and labetalol (10 mg/kg s.c.) for 5 days with sample collection and analysis. Plasma was also taken from healthy pregnant women and patients with ICP. Administration of labetalol to mice with EE cholestasis aggravated the increase in BA plasma concentrations by induction of hepatic Mrp4 efflux transporter. Labetalol potentiated the increment of sEng plasma levels induced by estrogen. Increased plasma levels of sEng were also observed in patients with ICP. Moreover, increased plasma levels of human sEng in transgenic mice aggravated estrogen-induced cholestasis in labetalol-treated mice and increased BA concentration in plasma via enhanced reabsorption of BAs in the ileum due to the upregulation of the Asbt transporter. In conclusion, we demonstrated that labetalol increases plasma concentrations of BAs in estrogen-induced cholestasis, and sEng aggravates this retention. Importantly, increased sEng levels in experimental and clinical forms of ICPs might present a novel mechanism explaining the coincidence of ICP with preeclampsia. Our data encourage BA monitoring in the plasma of pregnant women with preeclampsia and labetalol therapy.
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Affiliation(s)
- Ivone Cristina Igreja Sá
- Department of Biological and Medical Sciences, Faculty of Pharmacy in Hradec Kralove, Charles University, Hradec Kralove, Czechia
| | - Katarina Tripska
- Department of Biological and Medical Sciences, Faculty of Pharmacy in Hradec Kralove, Charles University, Hradec Kralove, Czechia
| | - Fatemeh Alaei Faradonbeh
- Department of Pharmacology, Faculty of Medicine in Hradec Kralove, Charles University, Hradec Kralove, Czechia
| | - Milos Hroch
- Department of Biochemistry, Faculty of Medicine in Hradec Kralove, Charles University, Hradec Kralove, Czechia
| | - Hana Lastuvkova
- Department of Pharmacology, Faculty of Medicine in Hradec Kralove, Charles University, Hradec Kralove, Czechia
| | - Jolana Schreiberova
- Department of Pharmacology, Faculty of Medicine in Hradec Kralove, Charles University, Hradec Kralove, Czechia
| | - Marian Kacerovsky
- Department of Obstetrics and Gynecology, University Hospital Hradec Kralove, Faculty of Medicine in Hradec Kralove, Charles University, Hradec Kralove, Czechia
| | - Miguel Pericacho
- Biomedical Research Institute of Salamanca and Renal and Cardiovascular Physiopathology Unit, Department of Physiology and Pharmacology, University of Salamanca, Salamanca, Spain
| | - Petr Nachtigal
- Department of Biological and Medical Sciences, Faculty of Pharmacy in Hradec Kralove, Charles University, Hradec Kralove, Czechia,*Correspondence: Stanislav Micuda, ; Petr Nachtigal,
| | - Stanislav Micuda
- Department of Pharmacology, Faculty of Medicine in Hradec Kralove, Charles University, Hradec Kralove, Czechia,*Correspondence: Stanislav Micuda, ; Petr Nachtigal,
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Role of Hepatocyte Transporters in Drug-Induced Liver Injury (DILI)-In Vitro Testing. Pharmaceutics 2022; 15:pharmaceutics15010029. [PMID: 36678658 PMCID: PMC9866820 DOI: 10.3390/pharmaceutics15010029] [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: 12/05/2022] [Revised: 12/16/2022] [Accepted: 12/20/2022] [Indexed: 12/24/2022] Open
Abstract
Bile acids and bile salts (BA/BS) are substrates of both influx and efflux transporters on hepatocytes. Canalicular efflux transporters, such as BSEP and MRP2, are crucial for the removal of BA/BS to the bile. Basolateral influx transporters, such as NTCP, OATP1B1/1B3, and OSTα/β, cooperate with canalicular transporters in the transcellular vectorial flux of BA/BS from the sinusoids to the bile. The blockage of canalicular transporters not only impairs the bile flow but also causes the intracellular accumulation of BA/BS in hepatocytes that contributes to, or even triggers, liver injury. In the case of BA/BS overload, the efflux of these toxic substances back to the blood via MRP3, MRP4, and OST α/β is considered a relief function. FXR, a key regulator of defense against BA/BS toxicity suppresses de novo bile acid synthesis and bile acid uptake, and promotes bile acid removal via increased efflux. In drug development, the early testing of the inhibition of these transporters, BSEP in particular, is important to flag compounds that could potentially inflict drug-induced liver injury (DILI). In vitro test systems for efflux transporters employ membrane vesicles, whereas those for influx transporters employ whole cells. Additional in vitro pharmaceutical testing panels usually include cellular toxicity tests using hepatocytes, as well as assessments of the mitochondrial toxicity and accumulation of reactive oxygen species (ROS). Primary hepatocytes are the cells of choice for toxicity testing, with HepaRG cells emerging as an alternative. Inhibition of the FXR function is also included in some testing panels. The molecular weight and hydrophobicity of the drug, as well as the steady-state total plasma levels, may positively correlate with the DILI potential. Depending on the phase of drug development, the physicochemical properties, dosing, and cut-off values of BSEP IC50 ≤ 25-50 µM or total Css,plasma/BSEP IC50 ≥ 0.1 may be an indication for further testing to minimize the risk of DILI liability.
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Cheng J, Gong L, Mi X, Wu X, Zheng J, Yang W. Case series of progressive familial intrahepatic cholestasis type 3: Characterization of variants in ABCB4 in China. Front Med (Lausanne) 2022; 9:962408. [PMID: 36569137 PMCID: PMC9774490 DOI: 10.3389/fmed.2022.962408] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 11/09/2022] [Indexed: 12/13/2022] Open
Abstract
Objective To improve the accuracy of the diagnosis of familial progressive intrahepatic cholestasis type 3 (PFIC3, https://www.omim.org/entry/602347). Materials and methods Between September 2019 and March 2021, we recruited four patients with PFIC3 from two liver centers in East China. Molecular genetic findings of ATP-binding cassette subfamily B member 4 [ATP binding cassette transporter A4 (ABCB4), https://www.omim.org/entry/171060] were prospectively examined, and clinical records, laboratory readouts, and macroscopic and microscopic appearances of the liver were analyzed. Results Four patients experienced cholestasis, mild jaundice, and elevated levels of serum direct bilirubin, γ-glutamyltransferase, or total bile acids. All patients had moderate-to-severe liver fibrosis or biliary cirrhosis, and their liver biopsy specimens stained positive with rhodamine. Molecular immunohistochemistry revealed reduced or absent MDR3 expression in all liver specimens. A novel mutation of ABCB4 (c.1560 + 2T > A) was identified in patients with PFIC3, which is of high clinical significance and may help understand mutant ABCB4 pathogenesis. Conclusion MDR3 immunohistochemistry and molecular genetic analyses of ABCB4 are essential for the accurate diagnosis of PFIC3.
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Affiliation(s)
- Jinlin Cheng
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Ling Gong
- Department of Infectious Diseases, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China
| | - Xiaoxiao Mi
- Department of Translational Medicine Platform, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China
| | - Xiangyan Wu
- Department of Pathology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China
| | - Jun Zheng
- Department of Pathology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China
| | - Wenjun Yang
- Department of Pathology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China,*Correspondence: Wenjun Yang,
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18
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Zhao Y, Chen L. Effects of intestinal bacteria on cardiovascular disease. Biotechnol Genet Eng Rev 2022; 38:270-287. [PMID: 35775836 DOI: 10.1080/02648725.2022.2074696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
In the long process of human evolution, the Intestinal Bacteria has become intimately related to human health, producing many metabolites in the intestines that can affect cardiovascular disease. Today, the incidence of cardiovascular disease is rising, its treatment is becoming increasingly important, and new therapeutic targets are needed. Here we describe the effects of trimethylamine oxide (TMAO), lipid metabolism, phenolic compounds, indole sulfate (IS), oleuropein (OL), and hydroxytyrosol (HT) on atherosclerosis, heart failure, hypertension, and other cardiovascular diseases, as well as their mechanism of action. This study provides new ideas, new methods, and new directions for the treatment of cardiovascular disease.
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Affiliation(s)
- Yiyi Zhao
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, China
| | - Liqun Chen
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, China
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Zhang Y, Chen SJ, Chen C, Chen XQ, Chatterjee S, Shuster DJ, Dexter H, Armstrong L, Joshi EM, Yang Z, Shen H. Repression of Organic Anion Transporting Polypeptide (OATP) 1B Expression and Increase of Plasma Coproporphyrin Level as Evidence for OATP1B Downregulation in Cynomolgus Monkeys Treated with Chenodeoxycholic Acid. Drug Metab Dispos 2022; 50:1077-1086. [PMID: 35636769 DOI: 10.1124/dmd.122.000875] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Accepted: 05/12/2022] [Indexed: 11/22/2022] Open
Abstract
Farnesoid X receptor (FXR) is a nuclear receptor known to markedly alter expression of major transporters and enzymes in the liver. However, its effects toward organic anion transporting polypeptides (OATP) 1B1 and 1B3 remain poorly characterized. Therefore, the present study was aimed at determining the effects of chenodeoxycholic acid (CDCA), a naturally occurring FXR agonist, on OATP1B expression in cynomolgus monkeys. Multiple administrations of 50 and 100 mg/kg of CDCA were first shown to significantly repress mRNA expression of SLCO1B1/3 approximately 60% to 80% in monkey livers. It also suppressed cytochrome P450 (CYP)7A1-mRNA and induced OSTα/β-mRNA, which are well known targets of FXR and determinants of bile acid homeostasis. CDCA concomitantly decreased OATP1B protein abundance by approximately 60% in monkey liver. In contrast, multiple doses of 15 mg/kg rifampin (RIF), a pregnane X receptor agonist, had no effect on hepatic OATP1B protein, although it induced the intestinal P-glycoprotein and MR2 proteins by ∼2-fold. Moreover, multiple doses of CDCA resulted in a steady ∼2- to 10-fold increase of the OATP1B biomarkers coproporphyrins (CPs) in the plasma samples collected prior to each CDCA dose. Additionally, 3.4- to 11.2-fold increases of CPI and CPIII areas under the curve were observed after multiple administrations compared with the single dose and vehicle administration dosing groups. Taken together, these data suggest that CDCA represses the expression of OATP1B1 and OATP1B3 in monkeys. Further investigation of OATP1B downregulation by FXR in humans is warranted, as such downregulation effects may be involved in bile acid homeostasis and potential drug interactions in man. SIGNIFICANCE STATEMENT: Using gene expression and proteomics tools, as well as endogenous biomarker data, for the first time, we have demonstrated that OATP1B expression was suppressed and its activity was reduced in the cynomolgus monkeys following oral administration of 50 and 100 mg/kg/day of chenodeoxycholic acid (CDCA), a Farnesoid X receptor agonist, for 8 days. These results lead to a better understanding of OATP1B downregulation by CDCA and its role on bile acid and drug disposition.
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Affiliation(s)
- Yueping Zhang
- Drug Metabolism and Pharmacokinetics (Y.Z., C.C, E.M.J., Z.Y., H.S.), Discovery Toxicology (S.-J.C., L.A.), Discovery Pharmaceutics (X.-Q.C.), and Veterinary Sciences (D.J.S., H.D.), Bristol Myers Squibb Company, Princeton, New Jersey; and Drug Metabolism and Pharmacokinetics (S.-J.C.), Biocon Bristol Myers Squibb R&D Centre, Syngene International Ltd., Bangalore, India
| | - Shen-Jue Chen
- Drug Metabolism and Pharmacokinetics (Y.Z., C.C, E.M.J., Z.Y., H.S.), Discovery Toxicology (S.-J.C., L.A.), Discovery Pharmaceutics (X.-Q.C.), and Veterinary Sciences (D.J.S., H.D.), Bristol Myers Squibb Company, Princeton, New Jersey; and Drug Metabolism and Pharmacokinetics (S.-J.C.), Biocon Bristol Myers Squibb R&D Centre, Syngene International Ltd., Bangalore, India
| | - Cliff Chen
- Drug Metabolism and Pharmacokinetics (Y.Z., C.C, E.M.J., Z.Y., H.S.), Discovery Toxicology (S.-J.C., L.A.), Discovery Pharmaceutics (X.-Q.C.), and Veterinary Sciences (D.J.S., H.D.), Bristol Myers Squibb Company, Princeton, New Jersey; and Drug Metabolism and Pharmacokinetics (S.-J.C.), Biocon Bristol Myers Squibb R&D Centre, Syngene International Ltd., Bangalore, India
| | - Xue-Qing Chen
- Drug Metabolism and Pharmacokinetics (Y.Z., C.C, E.M.J., Z.Y., H.S.), Discovery Toxicology (S.-J.C., L.A.), Discovery Pharmaceutics (X.-Q.C.), and Veterinary Sciences (D.J.S., H.D.), Bristol Myers Squibb Company, Princeton, New Jersey; and Drug Metabolism and Pharmacokinetics (S.-J.C.), Biocon Bristol Myers Squibb R&D Centre, Syngene International Ltd., Bangalore, India
| | - Sagnik Chatterjee
- Drug Metabolism and Pharmacokinetics (Y.Z., C.C, E.M.J., Z.Y., H.S.), Discovery Toxicology (S.-J.C., L.A.), Discovery Pharmaceutics (X.-Q.C.), and Veterinary Sciences (D.J.S., H.D.), Bristol Myers Squibb Company, Princeton, New Jersey; and Drug Metabolism and Pharmacokinetics (S.-J.C.), Biocon Bristol Myers Squibb R&D Centre, Syngene International Ltd., Bangalore, India
| | - David J Shuster
- Drug Metabolism and Pharmacokinetics (Y.Z., C.C, E.M.J., Z.Y., H.S.), Discovery Toxicology (S.-J.C., L.A.), Discovery Pharmaceutics (X.-Q.C.), and Veterinary Sciences (D.J.S., H.D.), Bristol Myers Squibb Company, Princeton, New Jersey; and Drug Metabolism and Pharmacokinetics (S.-J.C.), Biocon Bristol Myers Squibb R&D Centre, Syngene International Ltd., Bangalore, India
| | - Heather Dexter
- Drug Metabolism and Pharmacokinetics (Y.Z., C.C, E.M.J., Z.Y., H.S.), Discovery Toxicology (S.-J.C., L.A.), Discovery Pharmaceutics (X.-Q.C.), and Veterinary Sciences (D.J.S., H.D.), Bristol Myers Squibb Company, Princeton, New Jersey; and Drug Metabolism and Pharmacokinetics (S.-J.C.), Biocon Bristol Myers Squibb R&D Centre, Syngene International Ltd., Bangalore, India
| | - Laura Armstrong
- Drug Metabolism and Pharmacokinetics (Y.Z., C.C, E.M.J., Z.Y., H.S.), Discovery Toxicology (S.-J.C., L.A.), Discovery Pharmaceutics (X.-Q.C.), and Veterinary Sciences (D.J.S., H.D.), Bristol Myers Squibb Company, Princeton, New Jersey; and Drug Metabolism and Pharmacokinetics (S.-J.C.), Biocon Bristol Myers Squibb R&D Centre, Syngene International Ltd., Bangalore, India
| | - Elizabeth M Joshi
- Drug Metabolism and Pharmacokinetics (Y.Z., C.C, E.M.J., Z.Y., H.S.), Discovery Toxicology (S.-J.C., L.A.), Discovery Pharmaceutics (X.-Q.C.), and Veterinary Sciences (D.J.S., H.D.), Bristol Myers Squibb Company, Princeton, New Jersey; and Drug Metabolism and Pharmacokinetics (S.-J.C.), Biocon Bristol Myers Squibb R&D Centre, Syngene International Ltd., Bangalore, India
| | - Zheng Yang
- Drug Metabolism and Pharmacokinetics (Y.Z., C.C, E.M.J., Z.Y., H.S.), Discovery Toxicology (S.-J.C., L.A.), Discovery Pharmaceutics (X.-Q.C.), and Veterinary Sciences (D.J.S., H.D.), Bristol Myers Squibb Company, Princeton, New Jersey; and Drug Metabolism and Pharmacokinetics (S.-J.C.), Biocon Bristol Myers Squibb R&D Centre, Syngene International Ltd., Bangalore, India
| | - Hong Shen
- Drug Metabolism and Pharmacokinetics (Y.Z., C.C, E.M.J., Z.Y., H.S.), Discovery Toxicology (S.-J.C., L.A.), Discovery Pharmaceutics (X.-Q.C.), and Veterinary Sciences (D.J.S., H.D.), Bristol Myers Squibb Company, Princeton, New Jersey; and Drug Metabolism and Pharmacokinetics (S.-J.C.), Biocon Bristol Myers Squibb R&D Centre, Syngene International Ltd., Bangalore, India
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20
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Li Y, Zhou J, Li T. Regulation of the HBV Entry Receptor NTCP and its Potential in Hepatitis B Treatment. Front Mol Biosci 2022; 9:879817. [PMID: 35495620 PMCID: PMC9039015 DOI: 10.3389/fmolb.2022.879817] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Accepted: 03/14/2022] [Indexed: 11/13/2022] Open
Abstract
Hepatitis B virus (HBV) is a globally prevalent human DNA virus responsible for more than 250 million cases of chronic liver infection, a condition that can lead to liver inflammation, cirrhosis, and hepatocellular carcinoma. Sodium taurocholate co-transporting polypeptide (NTCP), a transmembrane protein highly expressed in human hepatocytes and a mediator of bile acid transport, has been identified as the receptor responsible for the cellular entry of both HBV and its satellite, hepatitis delta virus (HDV). This has led to significant advances in our understanding of the HBV life cycle, especially the early steps of infection. HepG2-NTCP cells and human NTCP-expressing transgenic mice have been employed as the primary cell culture and animal models, respectively, for the study of HBV, and represent valuable approaches for investigating its basic biology and developing treatments for infection. However, the mechanisms involved in the regulation of NTCP transcription, translation, post-translational modification, and transport are still largely elusive. Improvements in our understanding of NTCP biology would likely facilitate the design of new therapeutic drugs for the prevention of the de novo infection of naïve hepatocytes. In this review, we provide critical findings regarding NTCP biology and discuss important questions that remain unanswered.
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Affiliation(s)
- Yan Li
- *Correspondence: Yan Li, ; Tianliang Li,
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21
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Shulpekova Y, Shirokova E, Zharkova M, Tkachenko P, Tikhonov I, Stepanov A, Sinitsyna A, Izotov A, Butkova T, Shulpekova N, Nechaev V, Damulin I, Okhlobystin A, Ivashkin V. A Recent Ten-Year Perspective: Bile Acid Metabolism and Signaling. Molecules 2022; 27:molecules27061983. [PMID: 35335345 PMCID: PMC8953976 DOI: 10.3390/molecules27061983] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 03/10/2022] [Accepted: 03/15/2022] [Indexed: 11/22/2022] Open
Abstract
Bile acids are important physiological agents required for the absorption, distribution, metabolism, and excretion of nutrients. In addition, bile acids act as sensors of intestinal contents, which are determined by the change in the spectrum of bile acids during microbial transformation, as well as by gradual intestinal absorption. Entering the liver through the portal vein, bile acids regulate the activity of nuclear receptors, modify metabolic processes and the rate of formation of new bile acids from cholesterol, and also, in all likelihood, can significantly affect the detoxification of xenobiotics. Bile acids not absorbed by the liver can interact with a variety of cellular recipes in extrahepatic tissues. This provides review information on the synthesis of bile acids in various parts of the digestive tract, its regulation, and the physiological role of bile acids. Moreover, the present study describes the involvement of bile acids in micelle formation, the mechanism of intestinal absorption, and the influence of the intestinal microbiota on this process.
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Affiliation(s)
- Yulia Shulpekova
- Chair of Internal Diseases Propedeutics, Gastroenterology and Hepatology, Sechenov First Moscow State Medical University (Sechenov University), 119048 Moscow, Russia; (Y.S.); (E.S.); (P.T.); (I.T.); (V.N.); (A.O.); (V.I.)
| | - Elena Shirokova
- Chair of Internal Diseases Propedeutics, Gastroenterology and Hepatology, Sechenov First Moscow State Medical University (Sechenov University), 119048 Moscow, Russia; (Y.S.); (E.S.); (P.T.); (I.T.); (V.N.); (A.O.); (V.I.)
| | - Maria Zharkova
- Department of Hepatology University Clinical Hospital No.2, Sechenov First Moscow State Medical University (Sechenov University), 119048 Moscow, Russia;
| | - Pyotr Tkachenko
- Chair of Internal Diseases Propedeutics, Gastroenterology and Hepatology, Sechenov First Moscow State Medical University (Sechenov University), 119048 Moscow, Russia; (Y.S.); (E.S.); (P.T.); (I.T.); (V.N.); (A.O.); (V.I.)
| | - Igor Tikhonov
- Chair of Internal Diseases Propedeutics, Gastroenterology and Hepatology, Sechenov First Moscow State Medical University (Sechenov University), 119048 Moscow, Russia; (Y.S.); (E.S.); (P.T.); (I.T.); (V.N.); (A.O.); (V.I.)
| | - Alexander Stepanov
- Biobanking Group, Branch of Institute of Biomedical Chemistry “Scientific and Education Center”, 109028 Moscow, Russia; (A.S.); (A.S.); (A.I.); (T.B.)
| | - Alexandra Sinitsyna
- Biobanking Group, Branch of Institute of Biomedical Chemistry “Scientific and Education Center”, 109028 Moscow, Russia; (A.S.); (A.S.); (A.I.); (T.B.)
- Correspondence: ; Tel.: +7-499-764-98-78
| | - Alexander Izotov
- Biobanking Group, Branch of Institute of Biomedical Chemistry “Scientific and Education Center”, 109028 Moscow, Russia; (A.S.); (A.S.); (A.I.); (T.B.)
| | - Tatyana Butkova
- Biobanking Group, Branch of Institute of Biomedical Chemistry “Scientific and Education Center”, 109028 Moscow, Russia; (A.S.); (A.S.); (A.I.); (T.B.)
| | | | - Vladimir Nechaev
- Chair of Internal Diseases Propedeutics, Gastroenterology and Hepatology, Sechenov First Moscow State Medical University (Sechenov University), 119048 Moscow, Russia; (Y.S.); (E.S.); (P.T.); (I.T.); (V.N.); (A.O.); (V.I.)
| | - Igor Damulin
- Branch of the V. Serbsky National Medical Research Centre for Psychiatry and Narcology, 127994 Moscow, Russia;
| | - Alexey Okhlobystin
- Chair of Internal Diseases Propedeutics, Gastroenterology and Hepatology, Sechenov First Moscow State Medical University (Sechenov University), 119048 Moscow, Russia; (Y.S.); (E.S.); (P.T.); (I.T.); (V.N.); (A.O.); (V.I.)
| | - Vladimir Ivashkin
- Chair of Internal Diseases Propedeutics, Gastroenterology and Hepatology, Sechenov First Moscow State Medical University (Sechenov University), 119048 Moscow, Russia; (Y.S.); (E.S.); (P.T.); (I.T.); (V.N.); (A.O.); (V.I.)
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Lipiński P, Ciara E, Jurkiewicz D, Płoski R, Wawrzynowicz-Syczewska M, Pawłowska J, Jankowska I. Progressive familial intrahepatic cholestasis type 3: Report of four clinical cases, novel ABCB4 variants and long-term follow-up. Ann Hepatol 2022; 25:100342. [PMID: 33757843 DOI: 10.1016/j.aohep.2021.100342] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 02/24/2021] [Accepted: 03/03/2021] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND OBJECTIVES Progressive familial intrahepatic cholestasis type 3 (PFIC-3) is a rare autosomal recessive cholestatic liver disorder caused by mutations in the ABCB4 gene. The aim of this study was to present the phenotypic and genotypic spectrum of 4 Polish PFIC-3 patients diagnosed in a one-referral centre. MATERIALS AND METHODS The study included 4 patients with cholestasis and pathogenic variants in the ABCB4 gene identified by next-generation sequencing (NGS) of a targeted-gene panel or whole exome sequencing (WES). Clinical, laboratory, histological, and molecular data were collected. RESULTS Four patients (three males) were identified. The age at first noted clinical signs and symptoms was 6, 2.5, 14, and 2 years respectively; the mean age was 6 years. Those signs and symptoms include pruritus (2 out of 4 patients) and hepatomegaly with splenomegaly (4 out of 4 patients). The age at the time of referral to our centre was 9, 3, 15, and 2.5 years respectively, while the mean age was 7 years. Chronic cholestatic liver disease of unknown aetiology was established in all of them. The NGS analysis was performed in all patients at the last follow-up visit. Three novel variants including c.902T>A, p.Met301Lys, c.3279+1G>A, p.?, and c.3524T>A, p.Leu1175His were identified. The time from the first consultation to the final diagnosis was 14, 9, 3, and 1 year respectively; the mean was 6.8 years. A detailed follow-up was presented. CONCLUSIONS The clinical phenotype of PFIC-3 could be variable. The clinical and biochemical diagnosis of PFIC-3 is difficult, thus the NGS study is very useful in making a proper diagnosis.
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Affiliation(s)
- Patryk Lipiński
- Department of Pediatrics, Nutrition and Metabolic Diseases, The Children's Memorial Health Institute, Warsaw, Poland; Department of Gastroenterology, Hepatology, Nutritional Disturbances and Pediatrics, Children's Memorial Health Institute, Warsaw, Poland.
| | - Elżbieta Ciara
- Department of Medical Genetics, The Children's Memorial Health Institute, Warsaw, Poland
| | - Dorota Jurkiewicz
- Department of Medical Genetics, The Children's Memorial Health Institute, Warsaw, Poland
| | - Rafał Płoski
- Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland
| | - Marta Wawrzynowicz-Syczewska
- Department of Infectious Diseases, Hepatology and Liver Transplantation, Pomeranian Medical University in Szczecin, Poland
| | - Joanna Pawłowska
- Department of Gastroenterology, Hepatology, Nutritional Disturbances and Pediatrics, Children's Memorial Health Institute, Warsaw, Poland
| | - Irena Jankowska
- Department of Gastroenterology, Hepatology, Nutritional Disturbances and Pediatrics, Children's Memorial Health Institute, Warsaw, Poland
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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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24
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Liu TF, He JJ, Wang L, Zhang LY. Novel ABCB4 mutations in an infertile female with progressive familial intrahepatic cholestasis type 3: A case report. World J Clin Cases 2022; 10:1998-2006. [PMID: 35317165 PMCID: PMC8891790 DOI: 10.12998/wjcc.v10.i6.1998] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Revised: 11/25/2021] [Accepted: 01/10/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Mutations that occur in the ABCB4 gene, which encodes multidrug-resistant protein 3, underlie the occurrence of progressive familial intrahepatic cholestasis type 3 (PFIC3). Clinical signs of intrahepatic cholestasis due to gene mutations typically first appear during infancy or childhood. Reports of PFIC3 occurring in adults are rare.
CASE SUMMARY This is a case study of a 32-year-old infertile female Chinese patient with a 15-year history of recurrent abnormal liver function. Her primary clinical signs were elevated levels of alkaline phosphatase and γ-glutamyl transpeptidase. Other possible reasons for liver dysfunction were eliminated in this patient, resulting in a diagnosis of PFIC3. The diagnosis was confirmed using gene detection and histological analyses. Assessments using genetic sequencing analysis indicated the presence of two novel heterozygous mutations in the ABCB4 gene, namely, a 2950C>T; p.A984V mutation (exon 24) and a 667A>G; p.I223V mutation (exon 7). After receiving ursodeoxycholic acid (UDCA) treatment, the patient's liver function indices improved, and she successfully became pregnant by in vitro fertilization. However, the patient developed intrahepatic cholestasis of pregnancy in the first trimester. Fortunately, treatment with UDCA was safe and effective.
CONCLUSION These novel ABCB4 heterozygous mutations have a variety of clinical phenotypes. Continued follow-up is essential for a comprehensive understanding of PFIC3.
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Affiliation(s)
- Tian-Fu Liu
- Department of Hepatology, Lanzhou University Second Hospital, Lanzhou 730030, Gansu Province, China
| | - Jing-Jing He
- Department of Hepatology, Lanzhou University Second Hospital, Lanzhou 730030, Gansu Province, China
| | - Liang Wang
- Department of Hepatology, Lanzhou University Second Hospital, Lanzhou 730030, Gansu Province, China
| | - Ling-Yi Zhang
- Department of Hepatology, Lanzhou University Second Hospital, Lanzhou 730030, Gansu Province, China
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Yan M, Guo L, Yang Y, Zhang B, Hou Z, Gao Y, Gu H, Gong H. Glycyrrhetinic Acid Protects α-Naphthylisothiocyanate- Induced Cholestasis Through Regulating Transporters, Inflammation and Apoptosis. Front Pharmacol 2021; 12:701240. [PMID: 34630081 PMCID: PMC8497752 DOI: 10.3389/fphar.2021.701240] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 08/31/2021] [Indexed: 11/13/2022] Open
Abstract
Glycyrrhetinic acid (GA), the active metabolic product of Glycyrrhizin (GL) that is the main ingredient of licorice, was reported to protect against α-naphthylisothiocyanate (ANIT)- induced cholestasis. However, its protective mechanism remains unclear. In our work, the cholestatic liver injury in mice was caused by ANIT and GA was used for the treatment. We assessed cholestatic liver injury specific indexes, histopathological changes, bile acid transporters, inflammation and apoptosis. The results of liver biochemical index and histopathological examination showed that GA markedly attenuated ANIT-induced liver injury. Mechanism research suggested that GA could activate the expression of farnesoid x receptor (FXR) and its downstream bile acids transporters Na+/taurocholate co-transporting polypeptide (NTCP), bile salt export pump (BSEP) and multidrug resistance-associated protein 2 (MRP2), as well as the nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream proteins MRP3, MRP4. These transporters play a vital role in mediating bile acid homeostasis in hepatocytes. Moreover, GA could significantly inhibit the ANIT-induced activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) inflammatory pathway and the increase of tumor necrosis factor-α (TNF-α) concentration in serum. Also, GA protected against ANIT-induced mitochondrial apoptosis by regulating the expression of Bcl-2, Bax, cleaved caspase 3 and cleaved caspase 9. In conclusion, GA alleviates the hepatotoxicity caused by ANIT by regulating bile acids transporters, inflammation and apoptosis, which suggests that GA may be a potential therapeutic agent for cholestasis.
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Affiliation(s)
- Miao Yan
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Lin Guo
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Yan Yang
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Bikui Zhang
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Zhenyan Hou
- Department of Pharmacy, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Yue Gao
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, China
| | - Hongmei Gu
- Chia Tai Tianqing Pharmaceutical Group Co. Ltd., Lianyungang, China
| | - Hui Gong
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
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Gertzen CGW, Gohlke H, Häussinger D, Herebian D, Keitel V, Kubitz R, Mayatepek E, Schmitt L. The many facets of bile acids in the physiology and pathophysiology of the human liver. Biol Chem 2021; 402:1047-1062. [PMID: 34049433 DOI: 10.1515/hsz-2021-0156] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 05/14/2021] [Indexed: 12/12/2022]
Abstract
Bile acids perform vital functions in the human liver and are the essential component of bile. It is therefore not surprising that the biology of bile acids is extremely complex, regulated on different levels, and involves soluble and membrane receptors as well as transporters. Hereditary disorders of these proteins manifest in different pathophysiological processes that result in liver diseases of varying severity. In this review, we summarize our current knowledge of the physiology and pathophysiology of bile acids with an emphasis on recently established analytical approaches as well as the molecular mechanisms that underlie signaling and transport of bile acids. In this review, we will focus on ABC transporters of the canalicular membrane and their associated diseases. As the G protein-coupled receptor, TGR5, receives increasing attention, we have included aspects of this receptor and its interaction with bile acids.
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Affiliation(s)
- Christoph G W Gertzen
- Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- Center for Structural Studies (CSS), Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Holger Gohlke
- Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- John von Neumann Institute for Computing (NIC), Jülich Supercomputing Centre (JSC), Institute of Biological Information Processing (IBI-7: Structural Biochemistry), Institute of Bio- and Geosciences (IBG-4: Bioinformatics), Forschungszentrum Jülich GmbH, Jülich, Germany
| | - Dieter Häussinger
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Düsseldorf, Germany
| | - Diran Herebian
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Verena Keitel
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Düsseldorf, Germany
| | - Ralf Kubitz
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Düsseldorf, Germany
| | - Ertan Mayatepek
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Lutz Schmitt
- Institute of Biochemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
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Hu T, Wang H. Hepatic Bile Acid Transporters in Drug‐Induced Cholestasis. TRANSPORTERS AND DRUG‐METABOLIZING ENZYMES IN DRUG TOXICITY 2021:307-337. [DOI: 10.1002/9781119171003.ch10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Abstract
OBJECTIVES Dubin-Johnson syndrome (DJS) is an autosomal recessive disorder in which multidrug-resistance-associated protein 2 (MRP2) deficiency causes an excretion disorder of conjugated bilirubin from hepatocytes into bile canaliculi. Its clinical presentation as neonatal cholestasis (NC) is rare but represents an important differential diagnosis. We aimed to define DJS-specific characteristics in NC, in particular in contrast to biliary atresia (BA) patients, and to highlight diagnostic tools that can help to avoid invasive diagnostic tests. METHODS We performed a review of case records from 2006 to 2020 and compared 4 DJS patients to 26 patients with proven BA consecutively diagnosed from 2014 to 2017. DJS was diagnosed by urine coproporphyrin analysis (UCA) and by genetic analysis (GA) for disease-associated ABCC2 variants. RESULTS Four male patients with NC were diagnosed with DJS by UCA and GA. DJS patients presenting as NC showed significantly lower values for aspartate aminotransferase (AST) (P < 0.001), for alanine aminotransferase (ALT) (P = 0.002) and for gamma-glutamyl transferase (GGT) (P < 0.001) compared with BA patients. Other examinations, however, could not clearly discriminate them (e.g.: stool colour, serum bile acids, total serum bilirubin). CONCLUSIONS DJS is not only a rare differential diagnosis in NC with a suspicious phenotype (almost normal AST, ALT) but also shows overlapping features with BA. It should, therefore, be considered in every infant with NC and an atypical liver enzyme pattern to protect patients from unnecessary, invasive examinations. For this, UCA is a fast and reliable diagnostic tool. Confirmation based on GA is recommended. DJS patients have a good long-term prognosis.
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Tran QH, Nguyen VG, Tran CM, Nguyen MN. Down-regulation of solute carrier family 10 member 1 is associated with early recurrence and poorer prognosis of hepatocellular carcinoma. Heliyon 2021; 7:e06463. [PMID: 33763615 PMCID: PMC7973870 DOI: 10.1016/j.heliyon.2021.e06463] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Revised: 02/07/2021] [Accepted: 03/05/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most frequent malignancies and the fourth-leading cancer-related death worldwide. Most patients with HCC are diagnosed at a late stage in which curable therapies are limited. Thus, identifying biomarkers for early diagnosis and prognosis of HCC is essential for improving the treatment effectiveness in patients with HCC. In this paper, the SLC10A1 expression levels in the cells and the tissues and their correlation with HCC were analyzed using bioinformatics tools. Clinical information data and gene expression profiles were retrieved from the Gene Expression Omnibus and The Cancer Genome Atlas. Chi-square tests, log-rank tests, and Kaplan-Meier curves were performed using R packages. In all statistical analyses, a p-value of less than 0.05 was considered significant. We found that SLC10A1 primarily expresses in the liver, especially on the plasma membrane. The expression levels of SLC10A1 in tumors were consistently lower than that in normal tissue. Down-regulation of SLC10A1 was correlated with a poor survival outcome [p = 4.50e-05] and recurrence-free survival [p = 8.0e-04] in patients with HCC. In addition, multivariate analysis indicated that the expression of SLC10A1 was an independent predictor for survival outcome [p = 2.17e-05] and recurrence-free survival [p = 1.63e-04]. We concluded that SLC10A1 is a potential biomarker for the early diagnosis and prognosis of HCC in the era of personalized medicine.
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Affiliation(s)
- Quynh Hoa Tran
- Department of Biotechnology, Ho Chi Minh City University of Food Industry, Tay Thanh, Tan Phu District, HCM City, Viet Nam
| | - Van Gio Nguyen
- Department of Biotechnology, Ho Chi Minh City University of Food Industry, Tay Thanh, Tan Phu District, HCM City, Viet Nam
| | - Cong Manh Tran
- Department of Biotechnology, Ho Chi Minh City University of Food Industry, Tay Thanh, Tan Phu District, HCM City, Viet Nam
| | - Minh Nam Nguyen
- School of Medicine, Vietnam National University HCM City, Linh Trung Ward, Thu Duc District, HCM City, Viet Nam
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Jain AK, Anand R, Lerret S, Yanni G, Chen JY, Mohammad S, Doyle M, Telega G, Horslen S. Outcomes following liver transplantation in young infants: Data from the SPLIT registry. Am J Transplant 2021; 21:1113-1127. [PMID: 32767649 PMCID: PMC7867666 DOI: 10.1111/ajt.16236] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 07/20/2020] [Accepted: 07/20/2020] [Indexed: 02/06/2023]
Abstract
Liver transplantation (LT) in young patients is being performed with greater frequency. We hypothesized that objective analysis of pre-, intra-, and postoperative events would help understand contributors to successful outcomes and guide transplant decision processes. We queried SPLIT registry for pediatric transplants between 2011 and 2018. Outcomes were compared for age groups: 0-<3, 3-<6, 6-<12 months, and 1-<3 years (Groups A, B, C, D respectively) and by weight categories: <5, 5-10, >10 kg; 1033 patients were available for analysis. Cholestatic disease and fulminant failure were highest in group A and those <5 kg; and biliary atresia in group C (72.8%). Group A had significantly higher life support dependence (34.6%; P < .001), listing as United Network for Organ Sharing status 1a/1b (70.4%; P < .001), and shortest wait times (P < .001). The median (interquartile range) for international normalized ratio and bilirubin were highest in group A (3.0 [2.1-3.9] and 16.7 [6.8-29.7] mg/dL) and those <5 kg (2.6 [1.8-3.4] and 13.5 [3.0-28.4] mg/dL). A pediatric end -stage liver disease score ≥40, postoperative hospital stays, rejection, and nonanastomotic biliary strictures were highest in group A with lowest survival at 93.1%. Infants 0 to <3 months and those <5 kg need more intensive care with lower survival and higher complications. Importantly, potential LT before reaching status 1a/1b and aggressive postoperative management may positively influence their outcomes.
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Affiliation(s)
- Ajay K. Jain
- Saint Louis University, Saint Louis, Missouri, USA
| | | | - Stacee Lerret
- Medical College of Wisconsin, Milwaukee, Wisconsin, USA.,Pediatric Gastroenterology, Hepatology and Nutrition, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - George Yanni
- Pediatrics, Children’s Hospital of Los Angeles, Los Angeles, California, USA
| | | | - Saeed Mohammad
- Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Majella Doyle
- Surgery, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Greg Telega
- Medical College of Wisconsin, Milwaukee, Wisconsin, USA.,Pediatric Gastroenterology, Hepatology and Nutrition, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Simon Horslen
- Liver and Small Bowel Transplantation, Seattle Children’s Hospital, Seattle, Washington, USA
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de Haan LR, Verheij J, van Golen RF, Horneffer-van der Sluis V, Lewis MR, Beuers UHW, van Gulik TM, Olde Damink SWM, Schaap FG, Heger M, Olthof PB. Unaltered Liver Regeneration in Post-Cholestatic Rats Treated with the FXR Agonist Obeticholic Acid. Biomolecules 2021; 11:biom11020260. [PMID: 33578971 PMCID: PMC7916678 DOI: 10.3390/biom11020260] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 01/25/2021] [Accepted: 02/02/2021] [Indexed: 12/29/2022] Open
Abstract
In a previous study, obeticholic acid (OCA) increased liver growth before partial hepatectomy (PHx) in rats through the bile acid receptor farnesoid X-receptor (FXR). In that model, OCA was administered during obstructive cholestasis. However, patients normally undergo PHx several days after biliary drainage. The effects of OCA on liver regeneration were therefore studied in post-cholestatic Wistar rats. Rats underwent sham surgery or reversible bile duct ligation (rBDL), which was relieved after 7 days. PHx was performed one day after restoration of bile flow. Rats received 10 mg/kg OCA per day or were fed vehicle from restoration of bile flow until sacrifice 5 days after PHx. Liver regeneration was comparable between cholestatic and non-cholestatic livers in PHx-subjected rats, which paralleled liver regeneration a human validation cohort. OCA treatment induced ileal Fgf15 mRNA expression but did not enhance post-PHx hepatocyte proliferation through FXR/SHP signaling. OCA treatment neither increased mitosis rates nor recovery of liver weight after PHx but accelerated liver regrowth in rats that had not been subjected to rBDL. OCA did not increase biliary injury. Conclusively, OCA does not induce liver regeneration in post-cholestatic rats and does not exacerbate biliary damage that results from cholestasis. This study challenges the previously reported beneficial effects of OCA in liver regeneration in cholestatic rats.
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Affiliation(s)
- Lianne R. de Haan
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing 314001, Zhejiang, China;
- Department of Surgery, Amsterdam UMC, Location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; (T.M.v.G.); (P.B.O.)
| | - Joanne Verheij
- Department of Pathology, Amsterdam UMC, Location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;
| | - Rowan F. van Golen
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands;
| | - Verena Horneffer-van der Sluis
- National Phenome Centre, Department of Metabolism, Digestion and Reproduction, Imperial College London, London W12 0NN, UK; (V.H.-v.d.S.); (M.R.L.)
| | - Matthew R. Lewis
- National Phenome Centre, Department of Metabolism, Digestion and Reproduction, Imperial College London, London W12 0NN, UK; (V.H.-v.d.S.); (M.R.L.)
| | - Ulrich H. W. Beuers
- Department of Gastroenterology & Hepatology and Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology & Metabolism, Amsterdam UMC, Location AMC, 1105 AZ Amsterdam, The Netherlands;
| | - Thomas M. van Gulik
- Department of Surgery, Amsterdam UMC, Location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; (T.M.v.G.); (P.B.O.)
| | - Steven W. M. Olde Damink
- Department of Surgery & NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, 6200 MD Maastricht, The Netherlands; (S.W.M.O.D.); (F.G.S.)
- Department of General, Visceral and Transplantation Surgery, RWTH University Hospital Aachen, 52074 Aachen, Germany
| | - Frank G. Schaap
- Department of Surgery & NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, 6200 MD Maastricht, The Netherlands; (S.W.M.O.D.); (F.G.S.)
- Department of General, Visceral and Transplantation Surgery, RWTH University Hospital Aachen, 52074 Aachen, Germany
| | - Michal Heger
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing 314001, Zhejiang, China;
- Department of Surgery, Amsterdam UMC, Location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; (T.M.v.G.); (P.B.O.)
- Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands
- Correspondence: or ; Tel.: +86-138-19345926 or +31-30-2533966
| | - Pim B. Olthof
- Department of Surgery, Amsterdam UMC, Location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; (T.M.v.G.); (P.B.O.)
- Department of Surgery, Erasmus Medical Center, 3015 GD Rotterdam, The Netherlands
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Hayashi H, Osaka S, Sakabe K, Fukami A, Kishimoto E, Aihara E, Sabu Y, Mizutani A, Kusuhara H, Naritaka N, Zhang W, Huppert SS, Sakabe M, Nakamura T, Hu YC, Mayhew C, Setchell K, Takebe T, Asai A. Modeling Human Bile Acid Transport and Synthesis in Stem Cell-Derived Hepatocytes with a Patient-Specific Mutation. Stem Cell Reports 2021; 16:309-323. [PMID: 33450190 PMCID: PMC7878720 DOI: 10.1016/j.stemcr.2020.12.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 12/13/2020] [Accepted: 12/14/2020] [Indexed: 01/13/2023] Open
Abstract
The bile salt export pump (BSEP) is responsible for the export of bile acid from hepatocytes. Impaired transcellular transport of bile acids in hepatocytes with mutations in BSEP causes cholestasis. Compensatory mechanisms to regulate the intracellular bile acid concentration in human hepatocytes with BSEP deficiency remain unclear. To define pathways that prevent cytotoxic accumulation of bile acid in hepatocytes, we developed a human induced pluripotent stem cell-based model of isogenic BSEP-deficient hepatocytes in a Transwell culture system. Induced hepatocytes (i-Heps) exhibited defects in the apical export of bile acids but maintained a low intracellular bile acid concentration by inducing basolateral export. Modeling the autoregulation of bile acids on hepatocytes, we found that BSEP-deficient i-Heps suppressed de novo bile acid synthesis using the FXR pathway via basolateral uptake and export without apical export. These observations inform the development of therapeutic targets to reduce the overall bile acid pool in patients with BSEP deficiency.
Human isogenic iPSCs were generated by CRISPR to study a truncating mutation of BSEP iPSC-derived hepatocytes recapitulate pathophysiology of BSEP deficiency in patients BSEP-deficient hepatocytes induce alternative basolateral bile acid export Activation of FXR suppresses de novo bile acid synthesis in BSEP-deficient hepatocytes
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Affiliation(s)
- Hisamitsu Hayashi
- Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo, Japan
| | - Shuhei Osaka
- Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo, Japan
| | - Kokoro Sakabe
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Aiko Fukami
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Eriko Kishimoto
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Eitaro Aihara
- College of Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Yusuke Sabu
- Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo, Japan
| | - Ayumu Mizutani
- Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo, Japan
| | - Hiroyuki Kusuhara
- Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo, Japan
| | | | - Wujuan Zhang
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; College of Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Stacey S Huppert
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; College of Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Masahide Sakabe
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Takahisa Nakamura
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; College of Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Yueh-Chiang Hu
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; College of Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Christopher Mayhew
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; College of Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Kenneth Setchell
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; College of Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Takanori Takebe
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; College of Medicine, University of Cincinnati, Cincinnati, OH, USA; Institute of Research, Tokyo Medical and Dental University, Tokyo, Japan
| | - Akihiro Asai
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
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Wei X, Ma Y, Dong Z, Wang G, Lan X, Liao Z, Chen M. Dehydrodiconiferyl alcohol, a lignan from Herpetospermum pedunculosum, alleviates cholestasis by activating pathways associated with the farnesoid X receptor. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2021; 80:153378. [PMID: 33113499 DOI: 10.1016/j.phymed.2020.153378] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 09/07/2020] [Accepted: 10/11/2020] [Indexed: 06/11/2023]
Abstract
BACKGROUND In our previous study, we demonstrated the hepatoprotective effect of Herpetospermum pedunculosum in cholestatic rats. A bioassay-guided study also led to the identification and isolation of a lignan, dihydrodiconiferyl alcohol (DA) from the seeds of H. pedunculosum. PURPOSE To investigate whether DA could alleviate cholestasis and determine the mechanisms underlying such action. METHODS Male Sprague-Dawley (SD) rats were administered with DA (10, 20 or 40 mg/kg) intragastrically once daily for 7 days prior to treatment with α-naphthylisothiocyanate (ANIT) (60 mg/kg). We then evaluated the levels of a range of serum indicators, determined bile flow, and carried out histopathological analyses. Western blotting was then used to investigate the levels of inflammatory mediators and the Farnesoid X Receptor (FXR), proteins involved in the downstream biosynthesis of bile acids, and a range of transport proteins. Molecular docking was used to simulate the interaction between DA and FXR. Cell viability of human hepatocytes (L-02) cells was determined by MTT. Then, we treated guggulsterone-inhibited L-02 cells, Si-FXR L-02 cells, and FXR-overexpression cells with the FXR agonist GW4064 (6 μM) or DA (25, 50 and 100 μM) for 24 h before detecting gene and protein expression by RT-PCR and western blotting, respectively. RESULTS DA significantly attenuated ANIT-induced cholestasis in SD rats by reducing liver function indicators in the serum, increasing bile flow, improving the recovery of histopathological injuries in the liver, and by alleviating pro-inflammatory cytokines in the liver. DA also increased the expression levels of FXR and altered the levels of downstream proteins in the liver tissues, thus indicating that DA might alleviate cholestasis by regulating the FXR. Molecular docking simulations predicted that DA was as an agonist of FXR. In vitro mechanical studies further showed that DA increased the mRNA and protein expression levels of FXR, Small Heterodimer Partner 1/2, Bile Salt Export Pump, Multidrug Resistance-associated Protein 2, and Na+/taurocholate Co-transporting Polypeptide, in both guggulsterone-inhibited and Si-FXR L-02 cells. Moreover, DA enhanced the mRNA and protein expression of FXR, and its downstream genes and proteins, in L-02 cells containing an FXR-overexpression plasmid. CONCLUSION DA may represent an effective agonist for FXR has significant therapeutic potential for the treatment of cholestatic liver injury.
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MESH Headings
- 1-Naphthylisothiocyanate/toxicity
- ATP Binding Cassette Transporter, Subfamily B, Member 11/metabolism
- Animals
- Bile/metabolism
- Bile Acids and Salts/metabolism
- Cholestasis, Intrahepatic/chemically induced
- Cholestasis, Intrahepatic/drug therapy
- Cholestasis, Intrahepatic/metabolism
- Cholestasis, Intrahepatic/pathology
- Cucurbitaceae/chemistry
- Hepatocytes/drug effects
- Humans
- Isoxazoles/pharmacology
- Liver/drug effects
- Liver/metabolism
- Liver/pathology
- Male
- Molecular Docking Simulation
- Phenols/chemistry
- Phenols/pharmacology
- Rats, Sprague-Dawley
- Receptors, Cytoplasmic and Nuclear/agonists
- Receptors, Cytoplasmic and Nuclear/chemistry
- Receptors, Cytoplasmic and Nuclear/genetics
- Receptors, Cytoplasmic and Nuclear/metabolism
- Rats
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Affiliation(s)
- Xiaodong Wei
- College of Pharmaceutical Sciences, Southwest University, No.2 Tiansheng Road, Chongqing 400715, PR China
| | - Yingxiong Ma
- College of Pharmaceutical Sciences, Southwest University, No.2 Tiansheng Road, Chongqing 400715, PR China
| | - Zhaoyue Dong
- College of Pharmaceutical Sciences, Southwest University, No.2 Tiansheng Road, Chongqing 400715, PR China
| | - Guowei Wang
- College of Pharmaceutical Sciences, Southwest University, No.2 Tiansheng Road, Chongqing 400715, PR China
| | - Xiaozhong Lan
- TAAHC-SWU Medicinal Plant R&D Center, Xizang Agriculture and Animal Husbandry College, Nyingchi, Tibet, PR China
| | - Zhihua Liao
- School of Life Sciences, Southwest University, Chongqing 400715, PR China
| | - Min Chen
- College of Pharmaceutical Sciences, Southwest University, No.2 Tiansheng Road, Chongqing 400715, PR China.
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Ali Y, Shams T, Wang K, Cheng Z, Li Y, Shu W, Bao X, Zhu L, Murray M, Zhou F. The involvement of human organic anion transporting polypeptides (OATPs) in drug-herb/food interactions. Chin Med 2020; 15:71. [PMID: 32670395 PMCID: PMC7346646 DOI: 10.1186/s13020-020-00351-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Accepted: 07/03/2020] [Indexed: 02/08/2023] Open
Abstract
Organic anion transporting polypeptides (OATPs) are important transporter proteins that are expressed at the plasma membrane of cells, where they mediate the influx of endogenous and exogenous substances including hormones, natural compounds and many clinically important drugs. OATP1A2, OATP2B1, OATP1B1 and OATP1B3 are the most important OATP isoforms and influence the pharmacokinetic performance of drugs. These OATPs are highly expressed in the kidney, intestine and liver, where they determine the distribution of drugs to these tissues. Herbal medicines are increasingly popular for their potential health benefits. Humans are also exposed to many natural compounds in fruits, vegetables and other food sources. In consequence, the consumption of herbal medicines or food sources together with a range of important drugs can result in drug-herb/food interactions via competing specific OATPs. Such interactions may lead to adverse clinical outcomes and unexpected toxicities of drug therapies. This review summarises the drug-herb/food interactions of drugs and chemicals that are present in herbal medicines and/or food in relation to human OATPs. This information can contribute to improving clinical outcomes and avoiding unexpected toxicities of drug therapies in patients.
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Affiliation(s)
- Youmna Ali
- Faculty of Medicine and Health, Sydney Pharmacy School, The University of Sydney, Camperdown, NSW 2006 Australia
| | - Tahiatul Shams
- Faculty of Medicine and Health, Sydney Pharmacy School, The University of Sydney, Camperdown, NSW 2006 Australia
| | - Ke Wang
- Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu China
| | - Zhengqi Cheng
- Faculty of Medicine and Health, Sydney Pharmacy School, The University of Sydney, Camperdown, NSW 2006 Australia
| | - Yue Li
- Faculty of Medicine and Health, Sydney Pharmacy School, The University of Sydney, Camperdown, NSW 2006 Australia
| | - Wenying Shu
- Faculty of Medicine and Health, Sydney Pharmacy School, The University of Sydney, Camperdown, NSW 2006 Australia.,Department of Pharmacy, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong Province 511400 China
| | - Xiaofeng Bao
- School of Pharmacy, Nantong University, Nantong, Jiangsu Province 226019 China
| | - Ling Zhu
- The University of Sydney, Save Sight Institute, Sydney, NSW 2000 Australia
| | - Michael Murray
- Faculty of Medicine and Health, Discipline of Pharmacology, The University of Sydney, Camperdown, NSW 2006 Australia
| | - Fanfan Zhou
- Faculty of Medicine and Health, Sydney Pharmacy School, The University of Sydney, Camperdown, NSW 2006 Australia
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Wei X, Fan X, Feng Z, Ma Y, Lan X, Chen M. Ethyl acetate extract of herpetospermum pedunculosum alleviates α-naphthylisothiocyanate-induced cholestasis by activating the farnesoid x receptor and suppressing oxidative stress and inflammation in rats. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2020; 76:153257. [PMID: 32534360 DOI: 10.1016/j.phymed.2020.153257] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 05/08/2020] [Accepted: 05/29/2020] [Indexed: 06/11/2023]
Abstract
BACKGROUND Traditionally, seeds of Herpetospermum pedunculosum were used to treat liver disease or cholepathy. Up to date, their protecting effect against cholestasis was remain unclarified. PURPOSE To investigate the efficacy, possible mechanisms, and active constituents of the ethyl acetate extract from the seeds of Herpetospermum pedunculosum (HPEAE), studies were carried out using cholestasis rat model induced by α-naphthylisothiocyanate (ANIT). METHODS Male rats were intragastrically treated with HPEAE (100, 200 or 400 mg/kg) once a day for 7 days and were modeled with ANIT (60 mg/kg). The levels of serum indicators, bile flow, and histopathology were evaluated. Indices of oxidative stress and inflammatory mediators were detected using the enzyme-linked immunosorbent assay. Western blotting method was employed for analyzing the protein levels in the signal pathways of farnesoid X receptor (FXR), kelch ech associating protein 1/nuclear factor erythroid 2-related factor 2 (Keap1/Nrf2) and nuclear factor κB (NF-κB). The chemical compositions of HPEAE was analyzed by HPLC, and partially chemical components of HPEAE were identified by comparisons of their retention times with the standards. The FXR agonistic activity of the identified compounds was evaluated in l-02 cells induced by guggulsterone using a high-content screening system. RESULTS The cholestasis caused by ANIT can be significantly ameliorated by restoring the liver function indexes of alanine transaminase, aspartate transaminase, alkaline phosphatase, gamma-glutamyltransferase, total bilirubin, direct bilirubin and total bile acid, which are dose-dependent, as well as pathological liver injury and bile flow. Mechanical studies suggested that HPEAE can activate the expression of FXR and then up regulate its downstream proteins (multidrug resistance-associated protein 2, bile salt export pump and Na+/taurocholate cotransporting polypeptide). Moreover, the levels of the active oxygen index glutathione, superoxide dismutase, glutathione peroxidase, catalase and malondialdehyde were markedly restored by treatment with HPEAE. Western blotting further confirmed that HPEAE up regulated the expression of quinone oxidoreductase 1, heme oxygenase 1 and Keap1, lowered the expression of Nrf2 and reduced oxidative stress. HPEAE also up regulated P-glycoprotein 65, phosphorylated P-glycoprotein 65 and inhibitor of NF-κB kinase α expression, down regulated inhibitor of NF-κB (IκB), restored inflammatory mediator tumor necrosis factor-α, interleukin-1β (IL-1β), IL-6 and IL-10, and reduced inflammatory response. Fifteen compounds were identified (12 lignans and 3 coumarins). Among them, five lignans exhibited the significant FXR agonistic activity in vitro. CONCLUSION HPEAE may alleviate the cholestasis and liver injury caused by ANIT in rats by activating FXR, as well as suppressing the Keap1/Nrf2 and NF-κB signaling pathways and lignans may be its main active components.
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Affiliation(s)
- Xiaodong Wei
- College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, P.R. China
| | - Xudong Fan
- College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, P.R. China
| | - Zhiying Feng
- College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, P.R. China
| | - Yingxiong Ma
- College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, P.R. China
| | - Xiaozhong Lan
- TAAHC-SWU Medicinal Plant R&D Center, XiZang Agriculture and Animal Husbandry College, Nyingchi, Tibet, P.R. China
| | - Min Chen
- College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, P.R. China.
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Quintero J, Juamperez J, Gonzales E, Julio E, Mercadal-Hally M, Collado-Hilly M, Marín-Sánchez A, Charco R. Successful Treatment with Rituximab and Immunoadsorption for an Auto-Antibody Induced Bile Salt Export Pump Deficiency in a Liver Transplanted Patient. Pediatr Gastroenterol Hepatol Nutr 2020; 23:174-179. [PMID: 32206630 PMCID: PMC7073374 DOI: 10.5223/pghn.2020.23.2.174] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Accepted: 12/12/2019] [Indexed: 12/11/2022] Open
Abstract
We present an 8 years old girl who was diagnosed at 6 months of age of Progressive Familial Intrahepatic Cholestasis type 2. Although liver transplantation (LT) was classically considered curative for these patients, cholestasis recurrence with normal gamma-glutamyl transpeptidase (GGT), mediated by anti-bile salt export pump (BSEP) antibodies after LT (auto-antibody Induced BSEP Deficiency, AIBD) has been recently reported. Our patient underwent LT at 14 months. During her evolution, patient presented three episodes of acute rejection. Seven years after the LT, the patient presented pruritus with cholestasis and elevation of liver enzymes with persistent normal GGT. Liver biopsy showed intrahepatic cholestasis and giant-cell transformation with very low BSEP activity. Auto-antibodies against BSEP were detected therefore an AIBD was diagnosed. She was treated with Rituximab and immunoadsorption with resolution of the AIBD. As a complication of the treatment she developed a pneumocystis infection successfully treated with corticoids, cotrimoxazol and anidulafungin.
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Affiliation(s)
- Jesús Quintero
- Pediatric Hepatology and Liver Transplantation Unit, Vall d'Hebron University Hospital, Universitat Autónoma de Barcelona, Barcelona, Spain
| | - Javier Juamperez
- Pediatric Hepatology and Liver Transplantation Unit, Vall d'Hebron University Hospital, Universitat Autónoma de Barcelona, Barcelona, Spain
| | - Emmanuel Gonzales
- Inserm Unité Mixte de Recherche 1193, Université Paris-Saclay, Orsay France
| | - Ecaterina Julio
- Pediatric Hepatology and Liver Transplantation Unit, Vall d'Hebron University Hospital, Universitat Autónoma de Barcelona, Barcelona, Spain
| | - Maria Mercadal-Hally
- Pediatric Hepatology and Liver Transplantation Unit, Vall d'Hebron University Hospital, Universitat Autónoma de Barcelona, Barcelona, Spain
| | | | - Ana Marín-Sánchez
- Department of Immunology, Vall d'Hebron University Hospital, Universitat Autónoma de Barcelona, Barcelona, Spain
| | - Ramon Charco
- Department of HPB Surgery and Trasplant, Vall d'Hebron University Hospital, Universitat Autónoma de Barcelona, Barcelona, Spain
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Rifampicin induces clathrin-dependent endocytosis and ubiquitin-proteasome degradation of MRP2 via oxidative stress-activated PKC-ERK/JNK/p38 and PI3K signaling pathways in HepG2 cells. Acta Pharmacol Sin 2020; 41:56-64. [PMID: 31316180 PMCID: PMC7468545 DOI: 10.1038/s41401-019-0266-0] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Accepted: 05/30/2019] [Indexed: 01/05/2023]
Abstract
It was reported that antituberculosis medicines could induce liver damage via oxidative stress. In this study, we investigated the effects of rifampicin (RFP) on the membrane expression of multidrug resistance-associated protein 2 (MRP2) and the relationship between oxidative stress and RFP-induced endocytosis of MRP2 in HepG2 cells. We found that RFP (12.5–50 μM) dose-dependently decreased the expression and membrane localization of MRP2 in HepG2 cells without changing the messenger RNA level. RFP (50 μM) induced oxidative stress responses that further activated the PKC-ERK/JNK/p38 (protein kinase C-extracellular signal-regulated kinase/c-JUN N-terminal kinase/p38) and PI3K (phosphoinositide 3-kinase) signaling pathways in HepG2 cells. Pretreatment with glutathione reduced ethyl ester (2 mM) not only reversed the changes in oxidative stress indicators and signaling molecules but also diminished RFP-induced reduction in green fluorescence intensity of MRP2. We conducted co-immunoprecipitation assays and revealed that a direct interaction existed among MRP2, clathrin, and adaptor protein 2 (AP2) in HepG2 cells, and their expression was clearly affected by the changes in intracellular redox levels. Knockdown of clathrin or AP2 with small interfering RNA attenuated RFP-induced decreases of membrane and total MRP2. We further demonstrated that RFP markedly increased the ubiquitin–proteasome degradation of MRP2 in HepG2 cells, which was mediated by the E3 ubiquitin ligase GP78, but not HRD1 or TEB4. In conclusion, this study demonstrates that RFP-induced oxidative stress activates the PKC-ERK/JNK/p38 and PI3K signaling pathways that leads to clathrin-dependent endocytosis and ubiquitination of MRP2 in HepG2 cells, which provides new insight into the mechanism of RFP-induced cholestasis.
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Structure of the human lipid exporter ABCB4 in a lipid environment. Nat Struct Mol Biol 2019; 27:62-70. [PMID: 31873305 DOI: 10.1038/s41594-019-0354-3] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Accepted: 11/22/2019] [Indexed: 02/08/2023]
Abstract
ABCB4 is an ATP-binding cassette transporter that extrudes phosphatidylcholine into the bile canaliculi of the liver. Its dysfunction or inhibition by drugs can cause severe, chronic liver disease or drug-induced liver injury. We determined the cryo-EM structure of nanodisc-reconstituted human ABCB4 trapped in an ATP-bound state at a resolution of 3.2 Å. The nucleotide binding domains form a closed conformation containing two bound ATP molecules, but only one of the ATPase sites contains bound Mg2+. The transmembrane domains adopt a collapsed conformation at the level of the lipid bilayer, but we observed a large, hydrophilic and fully occluded cavity at the level of the cytoplasmic membrane boundary, with no ligand bound. This indicates a state following substrate release but prior to ATP hydrolysis. Our results rationalize disease-causing mutations in human ABCB4 and suggest an 'alternating access' mechanism of lipid extrusion, distinct from the 'credit card swipe' model of other lipid transporters.
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Deferm N, De Vocht T, Qi B, Van Brantegem P, Gijbels E, Vinken M, de Witte P, Bouillon T, Annaert P. Current insights in the complexities underlying drug-induced cholestasis. Crit Rev Toxicol 2019; 49:520-548. [PMID: 31589080 DOI: 10.1080/10408444.2019.1635081] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Drug-induced cholestasis (DIC) poses a major challenge to the pharmaceutical industry and regulatory agencies. It causes both drug attrition and post-approval withdrawal of drugs. DIC represents itself as an impaired secretion and flow of bile, leading to the pathological hepatic and/or systemic accumulation of bile acids (BAs) and their conjugate bile salts. Due to the high number of mechanisms underlying DIC, predicting a compound's cholestatic potential during early stages of drug development remains elusive. A profound understanding of the different molecular mechanisms of DIC is, therefore, of utmost importance. Although many knowledge gaps and caveats still exist, it is generally accepted that alterations of certain hepatobiliary membrane transporters and changes in hepatocellular morphology may cause DIC. Consequently, liver models, which represent most of these mechanisms, are valuable tools to predict human DIC. Some of these models, such as membrane-based in vitro models, are exceptionally well-suited to investigate specific mechanisms (i.e. transporter inhibition) of DIC, while others, such as liver slices, encompass all relevant biological processes and, therefore, offer a better representation of the in vivo situation. In the current review, we highlight the principal molecular mechanisms associated with DIC and offer an overview and critical appraisal of the different liver models that are currently being used to predict the cholestatic potential of drugs.
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Affiliation(s)
- Neel Deferm
- Department of Pharmaceutical and Pharmacological Sciences, Drug Delivery and Disposition, KU Leuven, Leuven, Belgium
| | - Tom De Vocht
- Department of Pharmaceutical and Pharmacological Sciences, Drug Delivery and Disposition, KU Leuven, Leuven, Belgium
| | - Bing Qi
- Department of Pharmaceutical and Pharmacological Sciences, Drug Delivery and Disposition, KU Leuven, Leuven, Belgium
| | - Pieter Van Brantegem
- Department of Pharmaceutical and Pharmacological Sciences, Drug Delivery and Disposition, KU Leuven, Leuven, Belgium
| | - Eva Gijbels
- Entity of In Vitro Toxicology and Dermato-Cosmetology, Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Brussels, Belgium
| | - Mathieu Vinken
- Entity of In Vitro Toxicology and Dermato-Cosmetology, Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Brussels, Belgium
| | - Peter de Witte
- Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium
| | - Thomas Bouillon
- Department of Pharmaceutical and Pharmacological Sciences, Drug Delivery and Disposition, KU Leuven, Leuven, Belgium
| | - Pieter Annaert
- Department of Pharmaceutical and Pharmacological Sciences, Drug Delivery and Disposition, KU Leuven, Leuven, Belgium
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Kenna JG, Taskar KS, Battista C, Bourdet DL, Brouwer KLR, Brouwer KR, Dai D, Funk C, Hafey MJ, Lai Y, Maher J, Pak YA, Pedersen JM, Polli JW, Rodrigues AD, Watkins PB, Yang K, Yucha RW. Can Bile Salt Export Pump Inhibition Testing in Drug Discovery and Development Reduce Liver Injury Risk? An International Transporter Consortium Perspective. Clin Pharmacol Ther 2019; 104:916-932. [PMID: 30137645 PMCID: PMC6220754 DOI: 10.1002/cpt.1222] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2018] [Accepted: 08/06/2018] [Indexed: 12/15/2022]
Abstract
Bile salt export pump (BSEP) inhibition has emerged as an important mechanism that may contribute to the initiation of human drug‐induced liver injury (DILI). Proactive evaluation and understanding of BSEP inhibition is recommended in drug discovery and development to aid internal decision making on DILI risk. BSEP inhibition can be quantified using in vitro assays. When interpreting assay data, it is important to consider in vivo drug exposure. Currently, this can be undertaken most effectively by consideration of total plasma steady state drug concentrations (Css,plasma). However, because total drug concentrations are not predictive of pharmacological effect, the relationship between total exposure and BSEP inhibition is not causal. Various follow‐up studies can aid interpretation of in vitro BSEP inhibition data and may be undertaken on a case‐by‐case basis. BSEP inhibition is one of several mechanisms by which drugs may cause DILI, therefore, it should be considered alongside other mechanisms when evaluating possible DILI risk.
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Affiliation(s)
| | - Kunal S Taskar
- Mechanistic Safety and Disposition, IVIVT, GlaxoSmithKline, Ware, Hertfordshire, UK
| | - Christina Battista
- DILIsym Services Inc., a Simulations Plus Company, Research Triangle Park, North Carolina, USA
| | - David L Bourdet
- Drug Metabolism and Pharmacokinetics, Theravance Biopharma, South San Francisco, California, USA
| | - Kim L R Brouwer
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | | | - David Dai
- Clinical Pharmacology, Research and Development Sciences, Agios Pharmaceuticals, Cambridge, Massachusetts, USA
| | - Christoph Funk
- Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, Basel, Switzerland
| | - Michael J Hafey
- Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Inc, Kenilworth, New Jersey, USA
| | - Yurong Lai
- Drug Metabolism, Gilead Sciences Inc., Foster City, California, USA
| | - Jonathan Maher
- Safety Assessment, Genentech, South San Francisco, California, USA
| | - Y Anne Pak
- Lilly Research Laboratory, Lilly Corporate Center, Eli Lilly and Company, Indianapolis, Indiana, USA
| | - Jenny M Pedersen
- Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Novum, Huddinge, Sweden
| | - Joseph W Polli
- Mechanistic Safety and Drug Disposition, GlaxoSmithKline, King of Prussia, Pennsylvania, USA
| | | | - Paul B Watkins
- Institute for Drug Safety Sciences, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Kyunghee Yang
- DILIsym Services Inc., a Simulations Plus Company, Research Triangle Park, North Carolina, USA
| | - Robert W Yucha
- Takeda Pharmaceuticals, Global Drug Metabolism and Pharmacokinetics, Cambridge, Massachusetts, USA
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Abstract
The farnesoid X receptor (FXR, NR1H4) is a bile acid (BA)-activated transcription factor, which is essential for BA homeostasis. FXR and its hepatic and intestinal target genes, small heterodimer partner (SHP, NR0B2) and fibroblast growth factor 15/19 (Fgf15 in mice, FGF19 in humans), transcriptionally regulate BA synthesis, detoxification, secretion, and absorption in the enterohepatic circulation. Furthermore, FXR modulates a large variety of physiological processes, such as lipid and glucose homeostasis as well as the inflammatory response. Targeted deletion of FXR renders mice highly susceptible to cholic acid feeding resulting in cholestatic liver injury, weight loss, and increased mortality. Combined deletion of FXR and SHP spontaneously triggers early-onset intrahepatic cholestasis in mice resembling human progressive familial intrahepatic cholestasis (PFIC). Reduced expression levels and activity of FXR have been reported in human cholestatic conditions, such as PFIC type 1 and intrahepatic cholestasis of pregnancy. Recently, two pairs of siblings with homozygous FXR truncation or deletion variants were identified. All four children suffered from severe, early-onset PFIC and liver failure leading to death or need for liver transplantation before the age of 2. These findings underscore the central role of FXR as regulator of systemic and hepatic BA levels. Therefore, targeting FXR has been exploited in different animal models of both intrahepatic and obstructive cholestasis, and the first FXR agonist obeticholic acid (OCA) has been approved for the treatment of primary biliary cholangitis (PBC). Further FXR agonists as well as a FGF19 analogue are currently tested in clinical trials for different cholestatic liver diseases. This chapter will summarize the current knowledge on the role of FXR in cholestasis both in rodent models and in human diseases.
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Isoform-specific Inhibition of N-methyl-D-aspartate Receptors by Bile Salts. Sci Rep 2019; 9:10068. [PMID: 31296930 PMCID: PMC6624251 DOI: 10.1038/s41598-019-46496-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 06/18/2019] [Indexed: 12/27/2022] Open
Abstract
The N-methyl-D-aspartate subfamily of ionotropic glutamate receptors (NMDARs) is well known for its important roles in the central nervous system (CNS), e.g. learning and memory formation. Besides the CNS, NMDARs are also expressed in numerous peripheral tissues including the pancreas, kidney, stomach, and blood cells, where an understanding of their physiological and pathophysiological roles is only evolving. Whereas subunit composition increases functional diversity of NMDARs, a great number of endogenous cues tune receptor signaling. Here, we characterized the effects of the steroid bile salts cholate and chenodeoxycholate (CDC) on recombinantly expressed NMDARs of defined molecular composition. CDC inhibited NMDARs in an isoform-dependent manner, preferring GluN2D and GluN3B over GluN2A and GluN2B receptors. Determined IC50 values were in the range of bile salt serum concentrations in severe cholestatic disease states, pointing at a putative pathophysiological significance of the identified receptor modulation. Both pharmacological and molecular simulation analyses indicate that CDC acts allosterically on GluN2D, whereas it competes with agonist binding on GluN3B receptors. Such differential modes of inhibition may allow isoform-specific targeted interference with the NMDAR/bile salt interaction. In summary, our study provides further molecular insight into the modulation of NMDARs by endogenous steroids and points at a putative pathophysiological role of the receptors in cholestatic disease.
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Vitale G, Gitto S, Vukotic R, Raimondi F, Andreone P. Familial intrahepatic cholestasis: New and wide perspectives. Dig Liver Dis 2019; 51:922-933. [PMID: 31105019 DOI: 10.1016/j.dld.2019.04.013] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Revised: 04/01/2019] [Accepted: 04/12/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND Progressive familial intrahepatic cholestasis (PFIC) includes autosomal recessive cholestatic rare diseases of childhood. AIMS To update the panel of single genes mutations involved in familial cholestasis. METHODS PubMed search for "familial intrahepatic cholestasis" alone as well as in combination with other key words was performed considering primarily original studies and meta-analyses. RESULTS PFIC1 involves ATP8B1 gene encoding for aminophospholipid flippase FIC1. PFIC2 includes ABCB11 gene, encoding for protein functioning as bile salt export pump. PFIC3 is due to mutations of ABCB4 gene responsible for the synthesis of class III multidrug resistance P-glycoprotein flippase. PFIC4 and PFIC5 involve tight junction protein-2 gene and NR1H4 gene encoding for farnesoid X receptor. Benign Intrahepatic Cholestasis, Intrahepatic Cholestasis of Pregnancy and Low-phospholipid-associated cholelithiasis involve the same genes and are characterized by intermittent attacks of cholestasis, no progression to cirrhosis, reversible pregnancy-specific cholestasis and cholelithiasis in young people. Blood and liver tissue levels of bile-excreted drugs can be influenced by the presence of mutations in PFIC genes, causing drug-induced cholestasis. Mutations in PFIC genes might increase the risk of liver cancer. CONCLUSION There is a high proportion of unexplained cholestasis potentially caused by specific genetic pathophysiologic pathways. The use of next generation sequencing and whole-exome sequencing could improve the diagnostic process in this setting.
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Affiliation(s)
- Giovanni Vitale
- ITEC Unit, Department of Medical and Surgical Sciences, University of Bologna, Italy; Research Centre for the Study of Hepatitis, University of Bologna, Italy; End-stage Liver Disease Unit, Department of Medical and Surgical Sciences, Sant'Orsola-Malpighi Hospital, University of Bologna, Italy
| | - Stefano Gitto
- ITEC Unit, Department of Medical and Surgical Sciences, University of Bologna, Italy; Research Centre for the Study of Hepatitis, University of Bologna, Italy
| | - Ranka Vukotic
- ITEC Unit, Department of Medical and Surgical Sciences, University of Bologna, Italy; Research Centre for the Study of Hepatitis, University of Bologna, Italy
| | - Francesco Raimondi
- Bioquant Institute, Heidelberg University, Germany; Heidelberg University Biochemistry Center (BZH), Germany
| | - Pietro Andreone
- ITEC Unit, Department of Medical and Surgical Sciences, University of Bologna, Italy; Research Centre for the Study of Hepatitis, University of Bologna, Italy.
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Sjöstedt N, Salminen TA, Kidron H. Endogenous, cholesterol-activated ATP-dependent transport in membrane vesicles from Spodoptera frugiperda cells. Eur J Pharm Sci 2019; 137:104963. [PMID: 31226387 DOI: 10.1016/j.ejps.2019.104963] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Revised: 06/04/2019] [Accepted: 06/17/2019] [Indexed: 12/19/2022]
Abstract
Transport proteins of the ATP-binding cassette (ABC) family are found in all kingdoms of life. In humans, several ABC efflux transporters play a role in drug disposition and excretion. Therefore, in vitro methods have been developed to characterize the substrate and inhibitor properties of drugs with respect to these transporters. In the vesicular transport assay, transport is studied using inverted membrane vesicles produced from transporter overexpressing cell lines of both mammalian and insect origin. Insect cell expression systems benefit from a higher expression compared to background, but are not as well characterized as their mammalian counterparts regarding endogenous transport. Therefore, the contribution of this transport in the assay might be underappreciated. In this study, endogenous transport in membrane vesicles from Spodoptera frugiperda -derived Sf9 cells was characterized using four typical substrates of human ABC transporters: 5(6)-carboxy-2,'7'-dichlorofluorescein (CDCF), estradiol-17β-glucuronide, estrone sulfate and N-methyl-quinidine. Significant ATP-dependent transport was observed for three of the substrates with cholesterol-loading of the vesicles, which is sometimes used to improve the activity of human transporters expressed in Sf9 cells. The highest effect of cholesterol was on CDCF transport, and this transport in the cholesterol-loaded Sf9 vesicles was time and concentration dependent with a Km of 8.06 ± 1.11 μM. The observed CDCF transport was inhibited by known inhibitors of human ABCC transporters, but not by ABCB1 and ABCG2 inhibitors verapamil and Ko143, respectively. Two candidate genes for ABCC-type transporters in the S. frugiperda genome (SfABCC2 and SfABCC3) were identified based on sequence analysis as a hypothesis to explain the observed endogenous ABCC-type transport in Sf9 vesicles. Although further studies are needed to verify the role of SfABCC2 and SfABCC3 in Sf9 vesicles, the findings of this study highlight the need to carefully characterize background transport in Sf9 derived membrane vesicles to avoid false positive substrate findings for human ABC transporters studied with this overexpression system.
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Affiliation(s)
- Noora Sjöstedt
- Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
| | - Tiina A Salminen
- Structural Bioinformatics Laboratory, Biochemistry, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland
| | - Heidi Kidron
- Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
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Elßner C, Goeppert B, Longerich T, Scherr AL, Stindt J, Nanduri LK, Rupp C, Kather JN, Schmitt N, Kautz N, Breuhahn K, Ismail L, Heide D, Hetzer J, García-Beccaria M, Hövelmeyer N, Waisman A, Urbanik T, Mueller S, Gdynia G, Banales JM, Roessler S, Schirmacher P, Jäger D, Schölch S, Keitel V, Heikenwalder M, Schulze-Bergkamen H, Köhler BC. Nuclear Translocation of RELB Is Increased in Diseased Human Liver and Promotes Ductular Reaction and Biliary Fibrosis in Mice. Gastroenterology 2019; 156:1190-1205.e14. [PMID: 30445013 DOI: 10.1053/j.gastro.2018.11.018] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Revised: 10/25/2018] [Accepted: 11/01/2018] [Indexed: 12/19/2022]
Abstract
BACKGROUND & AIMS Cholangiocyte proliferation and ductular reaction contribute to the onset and progression of liver diseases. Little is known about the role of the transcription factor nuclear factor-κB (NF-κB) in this process. We investigated the activities of the RELB proto-oncogene NF-κB subunit in human cholangiocytes and in mouse models of liver disease characterized by a ductular reaction. METHODS We obtained liver tissue samples from patients with primary sclerosing cholangitis, primary biliary cholangitis, hepatitis B or C virus infection, autoimmune hepatitis, alcoholic liver disease, or without these diseases (controls) from a tissue bank in Germany. Tissues were analyzed by immunohistochemistry for levels of RELB and lymphotoxin β (LTB). We studied mice with liver parenchymal cell (LPC)-specific disruption of the cylindromatosis (CYLD) lysine 63 deubiquitinase gene (Cyld), with or without disruption of Relb (CyldΔLPC mice and Cyld/RelbΔLPC mice) and compared them with C57BL/6 mice (controls). Mice were fed 5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) or standard chow diets to induce biliary injury or were given injections of CCl4 to induce non-cholestatic liver fibrosis. Liver tissues were analyzed by histology, immunohistochemistry, immunoblots, in situ hybridization, and quantitative real-time polymerase chain reaction. Cholangiocytes were isolated from normal human liver, incubated with LTB receptor agonist, and transfected with small interfering RNAs to knock down RELB. RESULTS In liver tissues from patients with primary sclerosing cholangitis, primary biliary cholangitis, chronic infection with hepatitis B or C virus, autoimmune hepatitis, or alcoholic liver disease, we detected increased nuclear translocation of RELB and increased levels of LTB in cholangiocytes that formed reactive bile ducts compared with control liver tissues. Human cholangiocytes, but not those with RELB knockdown, proliferated with exposure to LTB. The phenotype of CyldΔLPC mice, which included ductular reaction, oval cell activation, and biliary fibrosis, was completely lost from Cyld/RelbΔLPC mice. Compared with livers from control mice, livers from CyldΔLPC mice (but not Cyld/RelbΔLPC mice) had increased levels of mRNAs encoding cytokines (LTB; CD40; and tumor necrosis factor superfamily [TNFSF] members TNFSF11 [RANKL], TNFSF13B [BAFF], and TNFSF14 [LIGHT]) produced by reactive cholangiocytes. However, these strains of mice developed similar levels of liver fibrosis in response to CCl4 exposure. CyldΔLPC mice and Cyld/RelbΔLPC mice had improved liver function on the DDC diet compared with control mice fed the DDC diet. CONCLUSION Reactive bile ducts in patients with chronic liver diseases have increased levels of LTB and nuclear translocation of RELB. RELB is required for the ductular reaction and development of biliary fibrosis in CyldΔLPC mice. Deletion of RELB and CYLD from LPCs protects mice from DDC-induced cholestatic liver fibrosis.
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Affiliation(s)
- Christin Elßner
- Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany; Liver Cancer Center Heidelberg, University Hospital Heidelberg, Heidelberg, Germany
| | - Benjamin Goeppert
- Liver Cancer Center Heidelberg, University Hospital Heidelberg, Heidelberg, Germany; Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Thomas Longerich
- Liver Cancer Center Heidelberg, University Hospital Heidelberg, Heidelberg, Germany; Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Anna-Lena Scherr
- Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany
| | - Jan Stindt
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
| | - Lahiri Kanth Nanduri
- German Cancer Consortium (DKTK) and Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Medical Faculty, Technical University Dresden, Dresden, Germany
| | - Christian Rupp
- Department of Internal Medicine IV, University Hospital Heidelberg, Heidelberg, Germany
| | - Jakob Nikolas Kather
- Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany
| | - Nathalie Schmitt
- Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany
| | - Nicole Kautz
- Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany
| | - Kai Breuhahn
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Lars Ismail
- Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany
| | - Danijela Heide
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Jenny Hetzer
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - María García-Beccaria
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Nadine Hövelmeyer
- Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University of Mainz, Mainz, Germany
| | - Ari Waisman
- Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University of Mainz, Mainz, Germany
| | - Toni Urbanik
- Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany
| | - Sebastian Mueller
- Department of Medicine, Salem Medical Center and Center for Alcohol Research and Liver Disease, University of Heidelberg, Germany
| | - Georg Gdynia
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Jesus M Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute-Donostia University Hospital, University of the Basque Country (UPV-EHU) CIBERehd, IKERBASQUE, San Sebastian, Spain
| | - Stephanie Roessler
- Liver Cancer Center Heidelberg, University Hospital Heidelberg, Heidelberg, Germany; Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Peter Schirmacher
- Liver Cancer Center Heidelberg, University Hospital Heidelberg, Heidelberg, Germany; Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Dirk Jäger
- Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany; Liver Cancer Center Heidelberg, University Hospital Heidelberg, Heidelberg, Germany
| | - Sebastian Schölch
- German Cancer Consortium (DKTK) and Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Medical Faculty, Technical University Dresden, Dresden, Germany; Department of Surgery, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Verena Keitel
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
| | - Mathias Heikenwalder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | | | - Bruno Christian Köhler
- Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany; Liver Cancer Center Heidelberg, University Hospital Heidelberg, Heidelberg, Germany.
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Sohn MJ, Woo MH, Seong MW, Park SS, Kang GH, Moon JS, Ko JS. Benign Recurrent Intrahepatic Cholestasis Type 2 in Siblings with Novel ABCB11 Mutations. Pediatr Gastroenterol Hepatol Nutr 2019; 22:201-206. [PMID: 30899697 PMCID: PMC6416387 DOI: 10.5223/pghn.2019.22.2.201] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2018] [Revised: 05/28/2018] [Accepted: 06/27/2018] [Indexed: 12/16/2022] Open
Abstract
Benign recurrent intrahepatic cholestasis (BRIC), a rare cause of cholestasis, is characterized by recurrent episodes of cholestasis without permanent liver damage. BRIC type 2 (BRIC2) is an autosomal recessive disorder caused by ABCB11 mutations. A 6-year-old girl had recurrent episodes of jaundice. At two months of age, jaundice and hepatosplenomegaly developed. Liver function tests showed cholestatic hepatitis. A liver biopsy revealed diffuse giant cell transformation, bile duct paucity, intracytoplasmic cholestasis, and periportal fibrosis. An ABCB11 gene study revealed novel compound heterozygous mutations, including c.2075+3A>G in IVS17 and p.R1221K. Liver function test results were normal at 12 months of age. At six years of age, steatorrhea, jaundice, and pruritus developed. Liver function tests improved following administration of phenylbutyrate and rifampicin. Her younger brother developed jaundice at two months of age and his genetic tests revealed the same mutations as his sister. This is the first report of BRIC2 confirmed by ABCB11 mutations in Korean siblings.
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Affiliation(s)
- Min Ji Sohn
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | - Min Hyung Woo
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | - Moon-Woo Seong
- Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Sung Sup Park
- Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Gyeong Hoon Kang
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
| | - Jin Soo Moon
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | - Jae Sung Ko
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
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Gan L, Pan S, Cui J, Bai J, Jiang P, He Y. Functional analysis of the correlation between ABCB11 gene mutation and primary intrahepatic stone. Mol Med Rep 2018; 19:195-204. [PMID: 30431138 PMCID: PMC6297787 DOI: 10.3892/mmr.2018.9661] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2018] [Accepted: 10/22/2018] [Indexed: 12/16/2022] Open
Abstract
The adenosine 5'‑triphosphate binding cassette subfamily B member (ABCB)11 gene is involved in bile transport, and mutations in this gene are associated with cholestasis and cholelithiasis. Therefore, the aim of the present study was to investigate the association between ABCB11 gene mutation and primary intrahepatic stone (PIS)s and to investigate the mechanism through which ABCB11 gene mutations affect the expression of the corresponding protein. Mutations of the ABCB11 gene in 443 PIS patients and 560 healthy participants were detected by exon sequencing. The expression levels of ABCB11 mRNA and bile salt export pump (BSEP) protein in the liver tissues of patients with PISs were measured by quantitative polymerase chain reaction and western blot analysis. The mutant plasmids constructed by site‑directed mutagenesis of the human BSEP gene were transfected into human embryonic kidney 293 (293) cells and Madin‑Darby canine kidney (MDCK) cells, and the expression and distribution of rs118109635 of BSEP was measured. There were two significant mutations in the ABCB11 gene of the PIS patients compared with the healthy population; a missense mutation, rs118109635 (P=0.025), and a synonymous mutation, rs497692 (P=0.006). The two mutations were associated with the occurrence of preoperative jaundice (P=0.026, and P=0.011, respectively). The expression levels of BSEP in PIS patients with the missense mutation rs118109635 was decreased, whereas its mRNA expression levels remained unchanged. In PIS patients with the synonymous mutation rs497692, the expression levels of ABCB11 were decreased at both the mRNA and protein level. It was also found that mutation A865V reduced the expression levels of BSEP in 293 cells at the cellular level; its distribution in MDCK cell membranes was decreased, whereas its mRNA levels remained unchanged. The mutated loci at rs118109635 and rs497692 of the ABCB11 gene were correlated with PISs, causing a decreased expression of BSEP and reduced distribution of the protein in the cell membrane. Therefore, mutations at rs118109635 and rs497692 of the ABCB11 gene may be risk factors for PISs.
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Affiliation(s)
- Lang Gan
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, P.R. China
| | - Shuguang Pan
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, P.R. China
| | - Jinchi Cui
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, P.R. China
| | - Jie Bai
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, P.R. China
| | - Peng Jiang
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, P.R. China
| | - Yu He
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, P.R. China
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Khabou B, Tabebi M, Siala-Sahnoun O, Mkaouar-Rebai E, Rebai A, Fakhfakh F. Potential dysfunctional effects of synonymous variants: Insights from an exhaustive in silico analysis of the ABCB4 gene. Ann Hum Genet 2018; 82:457-468. [PMID: 30079523 DOI: 10.1111/ahg.12276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Revised: 06/27/2018] [Accepted: 07/04/2018] [Indexed: 11/30/2022]
Abstract
The multiple drug resistance 3 (MDR3) protein is a canalicular phospholipid translocator involved in the bile secretion and encoded by the ABCB4 gene. Its deficiency is related to a large spectrum of liver diseases. Taking into account the increased evidence about the involvement of synonymous variants in inherited diseases, this study aims to explore the putative effects of silent genetic variants on the ABCB4 expression. We performed an exhaustive computational approach using ESE finder, RegRNA 2.0, MFOLD, SNPfold, and %MinMax software added to the measurement of the Relative Synonymous Codon Usage. This analysis included 216 synonymous variants distributed throughout the ABCB4 gene. Results have shown that 11 synonymous coding SNPs decrease the ESE activity, while 8 of them change the codon frequency. Besides, the c.24C>T variation, located 21 nucleotides downstream the start A (Adenine) U (Uracil) G (Glutamine) AUG causes an increase in the local stability. Moreover, the computational analysis of the 3'UTR region showed that six of the eight variants located in this region affected the Wild Type (WT) pattern of the miRNA targets sites and/or their proper display. The 26 sSNPs retained as putatively functional possessed a very low allele frequency, supporting their pathogenicity. In conclusion, the obtained results suggest that some synonymous SNPs in the ABCB4 gene, considered up to now as neutral, may be involved in the MDR3 deficiency.
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Affiliation(s)
- Boudour Khabou
- Laboratory of Molecular and Functional Genetics, Faculty of Sciences, University of Sfax, Tunisia
| | - Mouna Tabebi
- Department of clinical and experimental medicine, Faculty of health sciences, Linköping University, Sweden
| | - Olfa Siala-Sahnoun
- Laboratory of Molecular and Functional Genetics, Faculty of Sciences, University of Sfax, Tunisia
| | - Emna Mkaouar-Rebai
- Laboratory of Molecular and Functional Genetics, Faculty of Sciences, University of Sfax, Tunisia
| | - Ahmed Rebai
- Molecular and Cellular Screening Process Laboratory, Centre of Biotechnology of Sfax, Sfax, Tunisia
| | - Faiza Fakhfakh
- Laboratory of Molecular and Functional Genetics, Faculty of Sciences, University of Sfax, Tunisia
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New Insights in Genetic Cholestasis: From Molecular Mechanisms to Clinical Implications. Can J Gastroenterol Hepatol 2018; 2018:2313675. [PMID: 30148122 PMCID: PMC6083523 DOI: 10.1155/2018/2313675] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Revised: 07/10/2018] [Accepted: 07/17/2018] [Indexed: 02/06/2023] Open
Abstract
Cholestasis is characterised by impaired bile secretion and accumulation of bile salts in the organism. Hereditary cholestasis is a heterogeneous group of rare autosomal recessive liver disorders, which are characterised by intrahepatic cholestasis, pruritus, and jaundice and caused by defects in genes related to the secretion and transport of bile salts and lipids. Phenotypic manifestation is highly variable, ranging from progressive familial intrahepatic cholestasis (PFIC)-with onset in early infancy and progression to end-stage liver disease-to a milder intermittent mostly nonprogressive form known as benign recurrent intrahepatic cholestasis (BRIC). Cases have been reported of initially benign episodic cholestasis that subsequently transitions to a persistent progressive form of the disease. Therefore, BRIC and PFIC seem to represent two extremes of a continuous spectrum of phenotypes that comprise one disease. Thus far, five representatives of PFIC (named PFIC1-5) caused by pathogenic mutations present in both alleles of ATP8B1, ABCB11, ABCB4, TJP2, and NR1H4 have been described. In addition to familial intrahepatic cholestasis, partial defects in ATP8B1, ABCB11, and ABCB4 predispose patients to drug-induced cholestasis and intrahepatic cholestasis in pregnancy. This review summarises the current knowledge of the clinical manifestations, genetics, and molecular mechanisms of these diseases and briefly outlines the therapeutic options, both conservative and invasive, with an outlook for future personalised therapeutic strategies.
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Yu Y, Li S, Liang W. Bona fide receptor for hepatitis B and D viral infections: Mechanism, research models and molecular drug targets. Emerg Microbes Infect 2018; 7:134. [PMID: 30050063 PMCID: PMC6062556 DOI: 10.1038/s41426-018-0137-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Revised: 06/26/2018] [Accepted: 06/27/2018] [Indexed: 12/13/2022]
Abstract
Hepatitis B infections have become a serious public health issue globally, and the current first-line antiviral treatment for this disease is not a true cure. Recently, sodium taurocholate cotransporting polypeptide (NTCP), a liver-specific bile acid transporter, was identified as a bona fide receptor for hepatitis B virus (HBV) and its satellite virus, hepatitis delta virus (HDV). Identification of the HBV receptor has led to the development of robust cell cultures and provides a potential target for new treatments. This review summarizes the process by which NTCP was discovered and describes its clinical significance as the receptor for HBV and HDV entry.
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Affiliation(s)
- Yueran Yu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, China.,Shengzhou People's Hospital, Shengzhou Branch of the First Affiliated Hospital of Zhejiang University, Shengzhou, 312400, China
| | - Shangda Li
- Department of Psychiatry, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, China
| | - Weifeng Liang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, China. .,Shengzhou People's Hospital, Shengzhou Branch of the First Affiliated Hospital of Zhejiang University, Shengzhou, 312400, China.
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