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1
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Gruget C, Reddy BG, Moore JM. A structural and mechanistic model for BSEP dysfunction in PFIC2 cholestatic disease. Commun Biol 2025; 8:531. [PMID: 40195555 PMCID: PMC11977275 DOI: 10.1038/s42003-025-07908-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Accepted: 03/10/2025] [Indexed: 04/09/2025] Open
Abstract
BSEP (ABCB11) transports bile salts across the canalicular membrane of hepatocytes, where they are incorporated into bile. Biallelic mutations in BSEP can cause Progressive Familial Intrahepatic Cholestasis Type 2 (PFIC2), a rare pediatric disease characterized by hepatic bile acid accumulation leading to hepatotoxicity and, ultimately, liver failure. The most frequently occurring PFIC2 disease-causing mutations are missense mutations, which often display a phenotype with decreased protein expression and impaired maturation and trafficking to the canalicular membrane. To characterize the mutational effects on protein thermodynamic stability, we carried out biophysical characterization of 13 distinct PFIC2-associated variants using in-cell thermal shift (CETSA) measurements. These experiments reveal a cluster of residues localized to the NBD2-ICL2 interface, which exhibit severe destabilization relative to wild-type BSEP. A high-resolution (2.8 Å) cryo-EM structure provides a framework for rationalizing the CETSA results, revealing a novel, NBD2-localized mechanism through which the most severe missense patient mutations drive cholestatic disease. These findings suggest potential strategies for identifying mechanism-based small molecule correctors to address BSEP trafficking defects and advance novel therapies for PFIC2 and other cholestatic diseases.
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MESH Headings
- Humans
- Cholestasis, Intrahepatic/genetics
- Cholestasis, Intrahepatic/metabolism
- ATP Binding Cassette Transporter, Subfamily B, Member 11/genetics
- ATP Binding Cassette Transporter, Subfamily B, Member 11/metabolism
- ATP Binding Cassette Transporter, Subfamily B, Member 11/chemistry
- Mutation, Missense
- Cryoelectron Microscopy
- Models, Molecular
- Bile Acids and Salts/metabolism
- Mutation
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Affiliation(s)
| | | | - Jonathan M Moore
- Massachusetts Institute of Technology, Cambridge, MA, USA.
- Rectify Pharmaceuticals, Cambridge, MA, USA.
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2
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Hof WFJ, de Boer JF, Verkade HJ. Emerging drugs for the treatment of progressive familial intrahepatic cholestasis: a focus on phase II and III trials. Expert Opin Emerg Drugs 2024; 29:305-320. [PMID: 38571480 DOI: 10.1080/14728214.2024.2336986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Accepted: 03/27/2024] [Indexed: 04/05/2024]
Abstract
INTRODUCTION Progressive familial intrahepatic cholestasis (PFIC) is a group of disorders characterized by inappropriate bile formation, causing hepatic accumulation of bile acids and, subsequently, liver injury. Until recently, no approved treatments were available for these patients. AREAS COVERED Recent clinical trials for PFIC treatment have focused on intestine-restricted ileal bile acid transporter (IBAT) inhibitors. These compounds aim to reduce the pool size of bile acids by interrupting their enterohepatic circulation. Other emerging treatments in the pipeline include systemic IBAT inhibitors, synthetic bile acid derivatives, compounds targeting bile acid synthesis via the FXR/FGF axis, and chaperones/potentiators that aim to enhance the residual activity of the mutated transporters. EXPERT OPINION Substantial progress has been made in drug development for PFIC patients during the last couple of years. Although data concerning long-term efficacy are as yet only scarcely available, new therapies have demonstrated robust efficacy in a considerable fraction of patients at least on the shorter term. However, a substantial fraction of PFIC patients do not respond to these novel therapies and thus still requires surgical treatment, including liver transplantation before adulthood. Hence, there is still an unmet medical need for long-term effective medical, preferably non-surgical, treatment for all PFIC patients.
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Affiliation(s)
- Willemien F J Hof
- Department of Pediatrics, University Medical Center Groningen, Groningen, The Netherlands
| | - Jan Freark de Boer
- Department of Pediatrics, University Medical Center Groningen, Groningen, The Netherlands
- Department of Laboratory Medicine, University Medical Center Groningen, Groningen, The Netherlands
| | - Henkjan J Verkade
- Department of Pediatrics, University Medical Center Groningen, Groningen, The Netherlands
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3
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Abdelhamed W, El-Kassas M. Rare liver diseases in Egypt: Clinical and epidemiological characterization. Arab J Gastroenterol 2024; 25:75-83. [PMID: 38228442 DOI: 10.1016/j.ajg.2023.12.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 12/04/2023] [Accepted: 12/16/2023] [Indexed: 01/18/2024]
Abstract
Illnesses that afflict a tiny number of individuals are referred to as rare diseases (RDs), sometimes called orphan diseases. The local healthcare systems are constantly under financial, psychological, and medical strain due to low incidence rates, unusual presentations, flawed diagnostic standards, and a lack of treatment alternatives for these RDs. The effective management of the once widely spread viral hepatitis B and C has altered the spectrum of liver diseases in Egypt during the last several years. The detection of uncommon disorders such as autoimmune, cholestatic, and hereditary liver diseases has also been made easier by the increasing knowledge and greater accessibility of specific laboratory testing. Finally, despite Egypt's large population, there are more uncommon liver disorders than previously thought. This review article discusses the clinical and epidemiological characteristics of a few uncommon liver disorders and the information currently accessible concerning these illnesses in Egypt.
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Affiliation(s)
- Walaa Abdelhamed
- Endemic Medicine Department, Faculty of Medicine, Sohag University, Sohag, Egypt
| | - Mohamed El-Kassas
- Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo, Egypt.
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4
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Sohail I, Hassan MU, Schmid D, Chiba P. The noncanonical nucleotide binding site 1 of the bile salt export pump is optimized for proper function of the transporter. Cell Biol Int 2024; 48:638-646. [PMID: 38328902 DOI: 10.1002/cbin.12136] [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: 08/15/2023] [Revised: 12/19/2023] [Accepted: 01/28/2024] [Indexed: 02/09/2024]
Abstract
The bile salt export pump (ABCB11/BSEP) is a hepatocyte plasma membrane-resident protein translocating bile salts into bile canaliculi. The sequence alignment of the four full-length transporters of the ABCB subfamily (ABCB1, ABCB4, ABCB5 and ABCB11) indicates that the NBD-NBD contact interface of ABCB11 differs from that of other members in only four residues. Notably, these are all located in the noncanonical nucleotide binding site 1 (NBS1). Substitution of all four deviant residues with canonical ones (quadruple mutant) significantly decreased the transport activity of the protein. In this study, we mutated two deviant residues in the signature sequence to generate a double mutant (R1221G/E1223Q). Furthermore, a triple mutant (E502S/R1221G/E1223Q) was generated, in which the deviant residues of the signature sequence and Q-loop were mutated concurrently to canonical residues. The double and triple mutants showed 80% and 60%, respectively, of the activity of wild-type BSEP. As expected, an increasing number of mutations gradually impair transport as an intricate network of interactions within the ABC proteins ensures proper functioning.
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Affiliation(s)
- Imran Sohail
- Department of Zoology, Government College University Lahore, Lahore, Pakistan
- Institute of Medical Chemistry, Medical University of Vienna, Vienna, Austria
| | - Mahmood Ul Hassan
- Institute of Medical Chemistry, Medical University of Vienna, Vienna, Austria
- Institute of Industrial Biotechnology, Government College University Lahore, Lahore, Pakistan
| | - Diethart Schmid
- Institute of Physiology, Medical University of Vienna, Vienna, Austria
| | - Peter Chiba
- Institute of Medical Chemistry, Medical University of Vienna, Vienna, Austria
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5
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Kondou H, Nakano S, Mizuno T, Bessho K, Hasegawa Y, Nakazawa A, Tanikawa K, Azuma Y, Okamoto T, Inui A, Imagawa K, Kasahara M, Zen Y, Suzuki M, Hayashi H. Clinical symptoms, biochemistry, and liver histology during the native liver period of progressive familial intrahepatic cholestasis type 2. Orphanet J Rare Dis 2024; 19:57. [PMID: 38341604 PMCID: PMC10858576 DOI: 10.1186/s13023-024-03080-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Accepted: 02/05/2024] [Indexed: 02/12/2024] Open
Abstract
BACKGROUND Progressive familial intrahepatic cholestasis type 2 (PFIC2) is an ultra-rare disease caused by mutations in the ABCB11 gene. This study aimed to understand the course of PFIC2 during the native liver period. METHODS From November 2014 to October 2015, a survey to identify PFIC2 patients was conducted in 207 hospitals registered with the Japanese Society of Pediatric Gastroenterology, Hepatology, and Nutrition. Investigators retrospectively collected clinical data at each facility in November 2018 using pre-specified forms. RESULTS Based on the biallelic pathogenic variants in ABCB11 and/or no hepatic immunohistochemical detection of BSEP, 14 Japanese PFIC2 patients were enrolled at seven facilities. The median follow-up was 63.2 [47.7-123.3] months. The median age of disease onset was 2.5 [1-4] months. Twelve patients underwent living donor liver transplantation (LDLT), with a median age at LDLT of 9 [4-57] months. Two other patients received sodium 4-phenylbutyrate (NaPB) therapy and survived over 60 months with the native liver. No patients received biliary diversion. The cases that resulted in LDLT had gradually deteriorated growth retardation, biochemical tests, and liver histology since the initial visit. In the other two patients, jaundice, growth retardation, and most of the biochemical tests improved after NaPB therapy was started, but pruritus and liver fibrosis did not. CONCLUSIONS Japanese PFIC2 patients had gradually worsening clinical findings since the initial visit, resulting in LDLT during infancy. NaPB therapy improved jaundice and growth retardation but was insufficient to treat pruritus and liver fibrosis.
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Affiliation(s)
- Hiroki Kondou
- Department of Pediatrics, Kindai University Nara Hospital, Nara, Japan
| | - Satoshi Nakano
- Department of Pediatrics, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Tadahaya Mizuno
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo, Japan
| | - Kazuhiko Bessho
- Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Yasuhiro Hasegawa
- Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Atsuko Nakazawa
- Department of Clinical Research, Saitama Children's Medical Center, Saitama, Japan
| | - Ken Tanikawa
- Department of Diagnostic Pathology, Kurume University Hospital, Fukuoka, Japan
| | - Yoshihiro Azuma
- Department of Pediatrics, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
| | - Tatsuya Okamoto
- Department of Pediatric Surgery, Kyoto University Hospital, Kyoto, Japan
| | - Ayano Inui
- Department of Pediatric Hepatology and Gastroenterology, Saiseikai Yokohama City Eastern Hospital, Kanagawa, Japan
| | - Kazuo Imagawa
- Department of Pediatrics, University of Tsukuba Hospital, Ibaraki, Japan
| | - Mureo Kasahara
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| | - Yoh Zen
- Institute of Liver Studies, King's College Hospital and King's College London, London, UK
| | - Mitsuyoshi Suzuki
- Department of Pediatrics, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Hisamitsu Hayashi
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo, Japan.
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6
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Xie S, Wei S, Ma X, Wang R, He T, Zhang Z, Yang J, Wang J, Chang L, Jing M, Li H, Zhou X, Zhao Y. Genetic alterations and molecular mechanisms underlying hereditary intrahepatic cholestasis. Front Pharmacol 2023; 14:1173542. [PMID: 37324459 PMCID: PMC10264785 DOI: 10.3389/fphar.2023.1173542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Accepted: 05/16/2023] [Indexed: 06/17/2023] Open
Abstract
Hereditary cholestatic liver disease caused by a class of autosomal gene mutations results in jaundice, which involves the abnormality of the synthesis, secretion, and other disorders of bile acids metabolism. Due to the existence of a variety of gene mutations, the clinical manifestations of children are also diverse. There is no unified standard for diagnosis and single detection method, which seriously hinders the development of clinical treatment. Therefore, the mutated genes of hereditary intrahepatic cholestasis were systematically described in this review.
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Affiliation(s)
- Shuying Xie
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Shizhang Wei
- Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing, China
| | - Xiao Ma
- Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Ruilin Wang
- Department of Pharmacy, 5th Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Tingting He
- Department of Pharmacy, 5th Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Zhao Zhang
- Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Ju Yang
- Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jiawei Wang
- Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Lei Chang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Manyi Jing
- Department of Pharmacy, Chinese PLA General Hospital, Beijing, China
| | - Haotian Li
- Department of Pharmacy, Chinese PLA General Hospital, Beijing, China
| | - Xuelin Zhou
- Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Yanling Zhao
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
- Department of Pharmacy, Chinese PLA General Hospital, Beijing, China
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7
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Moore JM, Bell EL, Hughes RO, Garfield AS. ABC transporters: human disease and pharmacotherapeutic potential. Trends Mol Med 2023; 29:152-172. [PMID: 36503994 DOI: 10.1016/j.molmed.2022.11.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 10/24/2022] [Accepted: 11/01/2022] [Indexed: 12/12/2022]
Abstract
Adenosine triphosphate (ATP)-binding cassette (ABC) transporters are a 48-member superfamily of membrane proteins that actively transport a variety of biological substrates across lipid membranes. Their functional diversity defines an expansive involvement in myriad aspects of human biology. At least 21 ABC transporters underlie rare monogenic disorders, with even more implicated in the predisposition to and symptomology of common and complex diseases. Such broad (patho)physiological relevance places this class of proteins at the intersection of disease causation and therapeutic potential, underlining them as promising targets for drug discovery, as exemplified by the transformative CFTR (ABCC7) modulator therapies for cystic fibrosis. This review will explore the growing relevance of ABC transporters to human disease and their potential as small-molecule drug targets.
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8
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Freitas IN, da Silva Jr JA, de Oliveira KM, Lourençoni Alves B, Dos Reis Araújo T, Camporez JP, Carneiro EM, Davel AP. Insights by which TUDCA is a potential therapy against adiposity. Front Endocrinol (Lausanne) 2023; 14:1090039. [PMID: 36896173 PMCID: PMC9989466 DOI: 10.3389/fendo.2023.1090039] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Accepted: 02/10/2023] [Indexed: 02/23/2023] Open
Abstract
Adipose tissue is an organ with metabolic and endocrine activity. White, brown and ectopic adipose tissues have different structure, location, and function. Adipose tissue regulates energy homeostasis, providing energy in nutrient-deficient conditions and storing it in high-supply conditions. To attend to the high demand for energy storage during obesity, the adipose tissue undergoes morphological, functional and molecular changes. Endoplasmic reticulum (ER) stress has been evidenced as a molecular hallmark of metabolic disorders. In this sense, the ER stress inhibitor tauroursodeoxycholic acid (TUDCA), a bile acid conjugated to taurine with chemical chaperone activity, has emerged as a therapeutic strategy to minimize adipose tissue dysfunction and metabolic alterations associated with obesity. In this review, we highlight the effects of TUDCA and receptors TGR5 and FXR on adipose tissue in the setting of obesity. TUDCA has been demonstrated to limit metabolic disturbs associated to obesity by inhibiting ER stress, inflammation, and apoptosis in adipocytes. The beneficial effect of TUDCA on perivascular adipose tissue (PVAT) function and adiponectin release may be related to cardiovascular protection in obesity, although more studies are needed to clarify the mechanisms. Therefore, TUDCA has emerged as a potential therapeutic strategy for obesity and comorbidities.
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Affiliation(s)
- Israelle Netto Freitas
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas, Campinas, SP, Brazil
- Obesity and Comorbidities Research Center, University of Campinas, Campinas, SP, Brazil
| | | | | | | | | | - João Paulo Camporez
- Department of Physiology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil
| | - Everardo Magalhães Carneiro
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas, Campinas, SP, Brazil
- Obesity and Comorbidities Research Center, University of Campinas, Campinas, SP, Brazil
| | - Ana Paula Davel
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas, Campinas, SP, Brazil
- Obesity and Comorbidities Research Center, University of Campinas, Campinas, SP, Brazil
- *Correspondence: Ana Paula Davel,
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9
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Felzen A, van Wessel DB, Gonzales E, Thompson RJ, Jankowska I, Shneider BL, Sokal E, Grammatikopoulos T, Kadaristiana A, Jacquemin E, Spraul A, Lipiński P, Czubkowski P, Rock N, Shagrani M, Broering D, Nicastro E, Kelly D, Nebbia G, Arnell H, Fischler B, Hulscher JB, Serranti D, Arikan C, Polat E, Debray D, Lacaille F, Goncalves C, Hierro L, Muñoz Bartolo G, Mozer-Glassberg Y, Azaz A, Brecelj J, Dezsőfi A, Calvo PL, Grabhorn E, Hartleif S, van der Woerd WJ, Kamath BM, Wang JS, Li L, Durmaz Ö, Kerkar N, Jørgensen MH, Fischer R, Jimenez-Rivera C, Alam S, Cananzi M, Laverdure N, Ferreira CT, Guerrero FO, Wang H, Sency V, Kim KM, Chen HL, de Carvalho E, Fabre A, Bernabeu JQ, Zellos A, Alonso EM, Sokol RJ, Suchy FJ, Loomes KM, McKiernan PJ, Rosenthal P, Turmelle Y, Horslen S, Schwarz K, Bezerra JA, Wang K, Hansen BE, Verkade HJ. Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency. JHEP Rep 2022; 5:100626. [PMID: 36687469 PMCID: PMC9852554 DOI: 10.1016/j.jhepr.2022.100626] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 10/07/2022] [Accepted: 10/24/2022] [Indexed: 11/17/2022] Open
Abstract
Background & Aims Bile salt export pump (BSEP) deficiency frequently necessitates liver transplantation in childhood. In contrast to two predicted protein truncating mutations (PPTMs), homozygous p.D482G or p.E297G mutations are associated with relatively mild phenotypes, responsive to surgical interruption of the enterohepatic circulation (siEHC). The phenotype of patients with a compound heterozygous genotype of one p.D482G or p.E297G mutation and one PPTM has remained unclear. We aimed to assess their genotype-phenotype relationship. Methods From the NAPPED database, we selected patients with homozygous p.D482G or p.E297G mutations (BSEP1/1; n = 31), with one p.D482G or p.E297G, and one PPTM (BSEP1/3; n = 30), and with two PPTMs (BSEP3/3; n = 77). We compared clinical presentation, native liver survival (NLS), and the effect of siEHC on NLS. Results The groups had a similar median age at presentation (0.7-1.3 years). Overall NLS at age 10 years was 21% in BSEP1/3 vs. 75% in BSEP1/1 and 23% in BSEP3/3 (p <0.001). Without siEHC, NLS in the BSEP1/3 group was similar to that in BSEP3/3, but considerably lower than in BSEP1/1 (at age 10 years: 38%, 30%, and 71%, respectively; p = 0.003). After siEHC, BSEP1/3 and BSEP3/3 were associated with similarly low NLS, while NLS was much higher in BSEP1/1 (10 years after siEHC, 27%, 14%, and 92%, respectively; p <0.001). Conclusions Individuals with BSEP deficiency with one p.E297G or p.D482G mutation and one PPTM have a similarly severe disease course and low responsiveness to siEHC as those with two PPTMs. This identifies a considerable subgroup of patients who are unlikely to benefit from interruption of the enterohepatic circulation by either surgical or ileal bile acid transporter inhibitor treatment. Impact and implications This manuscript defines the clinical features and prognosis of individuals with BSEP deficiency involving the combination of one relatively mild and one very severe BSEP deficiency mutation. Until now, it had always been assumed that the mild mutation would be enough to ensure a relatively good prognosis. However, our manuscript shows that the prognosis of these patients is just as poor as that of patients with two severe mutations. They do not respond to biliary diversion surgery and will likely not respond to the new IBAT (ileal bile acid transporter) inhibitors, which have recently been approved for use in BSEP deficiency.
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Key Words
- ABCB11, ATP-binding cassette, sub-family B member 11
- ALT, alanine aminotransferase
- AST, aspartate aminotransferase
- BSEP
- BSEP, bile salt export pump
- ChiLDReN, Childhood Liver Disease Research Network
- GGT, gamma-glutamyltransferase
- HCC, hepatocellular carcinoma
- LTx, liver transplantation
- NAPPED, NAtural course and Prognosis of PFIC and Effect of biliary Diversion
- NLS, native liver survival
- PFIC2
- PFIC2, progressive familial intrahepatic cholestasis type 2
- PPTM, predicted protein truncating mutation
- REDCap, Research Electronic Data Capture
- TSB, total serum bilirubin
- UDCA, ursodeoxycholic acid
- compound heterozygosity
- genotype
- interruption of the enterohepatic circulation
- phenotype
- sBAs, serum bile acids
- siEHC, surgical interruption of the enterohepatic circulation
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Affiliation(s)
- Antonia Felzen
- Pediatric Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, the Netherlands
| | - Daan B.E. van Wessel
- Pediatric Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, the Netherlands
| | - Emmanuel Gonzales
- Pediatric Hepatology & Pediatric Liver Transplant Department, Centre de Référence de l'Atrésie des Voies Biliaires et des Cholestases Génétiques, Filière de Santé des Maladies Rares du Foie de l'enfant et de l'adulte, Assistance Publique-Hôpitaux de Paris, Faculté de Médecine Paris-Saclay, CHU Bicêtre, Paris, France,European Reference Network on Hepatological Diseases (ERN RARE-LIVER),INSERM, UMR-S 1193, Hepatinov, Université Paris-Saclay, Orsay, France
| | | | - Irena Jankowska
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER),Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, The Children’s Memorial Health Institute, Warsaw, Poland
| | - Benjamin L. Shneider
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA,Childhood Liver Disease Research Network (ChiLDReN)
| | - Etienne Sokal
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER),Pediatric Gastorenterology and Hepatology, Université Catholique de Louvain, Cliniques St Luc, Brussels, Belgium
| | | | | | - Emmanuel Jacquemin
- Pediatric Hepatology & Pediatric Liver Transplant Department, Centre de Référence de l'Atrésie des Voies Biliaires et des Cholestases Génétiques, Filière de Santé des Maladies Rares du Foie de l'enfant et de l'adulte, Assistance Publique-Hôpitaux de Paris, Faculté de Médecine Paris-Saclay, CHU Bicêtre, Paris, France,European Reference Network on Hepatological Diseases (ERN RARE-LIVER),INSERM, UMR-S 1193, Hepatinov, Université Paris-Saclay, Orsay, France
| | - Anne Spraul
- INSERM, UMR-S 1193, Hepatinov, Université Paris-Saclay, Orsay, France,Service de Biochemie, Bicêtre Hôspital, AP-HP, Université Paris-Sud, Paris-Saclay, Inserm UMR-S 1174, France
| | - Patryk Lipiński
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER),Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, The Children’s Memorial Health Institute, Warsaw, Poland
| | - Piotr Czubkowski
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER),Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, The Children’s Memorial Health Institute, Warsaw, Poland
| | - Nathalie Rock
- Pediatric Gastroenterology, Hepatology and Nutrition Unit, Division of Pediatric Specialties, Department of Pediatrics, Gynecology and Obstetrics, University Hospitals of Geneva, Switzerland
| | - Mohammad Shagrani
- Liver & SB Transplant & Hepatobiliary-Pancreatic Surgery, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia,Alfaisal University, College of Medicine, Riyadh, Saudi Arabia
| | - Dieter Broering
- Liver & SB Transplant & Hepatobiliary-Pancreatic Surgery, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia
| | - Emanuele Nicastro
- Pediatric Hepatology, Gastroenterology and Transplantation, ASST Papa Giovanni XXIII, Bergamo, Italy
| | - Deirdre Kelly
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER),Liver Unit, Birmingham Women’s and Children’s Hospital, Birmingham, United Kingdom
| | - Gabriella Nebbia
- Servizio Di Epatologia e Nutrizione Pediatrica, Fondazione Irccs Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - Henrik Arnell
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER),Pediatric Gastroenterology Hepatology and Nutrition, Astrid Lindgren Children’s Hospital, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden
| | - Björn Fischler
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER),Pediatric Gastroenterology Hepatology and Nutrition, Astrid Lindgren Children’s Hospital, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden
| | - Jan B.F. Hulscher
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER),Pediatric Surgery, University Medical Center Groningen, Groningen, the Netherlands
| | - Daniele Serranti
- Pediatric and Liver Unit, Meyer Children’s University Hospital of Florence, Florence, Italy
| | - Cigdem Arikan
- Koc University School of Medicine, Pediatric GI and Hepatology Liver Transplantation Center, Kuttam System in Liver Medicine, Istanbul, Turkey
| | - Esra Polat
- Pediatric Gastroenterology, Sancaktepe Training and Research Hospital, Istanbul, Turkey
| | - Dominique Debray
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER),Gastroenterology-Hepatology-Nutrition Unit, APHP-Necker Enfants Malades University Hospital, Paris, France
| | - Florence Lacaille
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER),Gastroenterology-Hepatology-Nutrition Unit, APHP-Necker Enfants Malades University Hospital, Paris, France
| | - Cristina Goncalves
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER),Previously Coimbra University Hospital Center, Coimbra, Portugal, Now Pediatric Gastroenterology/Hepatology Center Lisbon, Portugal
| | - Loreto Hierro
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER),Service of Pediatric Hepatology and Transplantation, Children's Hospital La Paz, La Paz University Hospital, Madrid, Spain
| | - Gema Muñoz Bartolo
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER),Service of Pediatric Hepatology and Transplantation, Children's Hospital La Paz, La Paz University Hospital, Madrid, Spain
| | - Yael Mozer-Glassberg
- Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center of Israel, Petah Tikva, Israel
| | - Amer Azaz
- Pediatric Gastroenterology, Hepatology and Nutrition, Sheikh Khalifa Medical City, Abu Dhabi, United Arab Emirates
| | - Jernej Brecelj
- Department of Gastroenterology, Hepatology and Nutrition, University Children's Hospital Ljubljana, and Department of Pediatrics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia,Department of Pediatrics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Antal Dezsőfi
- Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | - Pier Luigi Calvo
- Pediatic Gastroenterology Unit, Regina Margherita Children's Hospital, Azienda Ospedaliera Città Della Salute e Della Scienza University Hospital, Turin, Italy
| | - Enke Grabhorn
- Pediatric Hepatology and Liver Transplantation, University Medical Center Hamburg Eppendorf, Hamburg, Germany
| | - Steffen Hartleif
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER),Pediatric Gastroenterology and Hepatology, University Children’s Hospital Tυ¨bingen, University Medical Center Tυ¨bingen, Tυ¨bingen, Germany
| | - Wendy J. van der Woerd
- Pediatric Gastroenterology, Hepatology and Nutrition, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Binita M. Kamath
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA,Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children and the University of Toronto, Toronto, Canada
| | - Jian-She Wang
- Children’s Hospital of Fudan University, Shanghai, China
| | - Liting Li
- Children’s Hospital of Fudan University, Shanghai, China
| | - Özlem Durmaz
- Department of Child Health and Diseases, Gastroenterology, Hepatology and Nutrition, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Nanda Kerkar
- Pediatric Gastroenterology, Hepatology and Nutrition, University of Rochester Medical Center, Rochester, NY, USA
| | - Marianne Hørby Jørgensen
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER),Department of Pediatrics and Adolescent Medicine, Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark
| | - Ryan Fischer
- Pediatric Gastroenterology, Hepatology and Nutrition, Children's Mercy Hospital, Kansas City, MO, USA
| | - Carolina Jimenez-Rivera
- Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Canada
| | - Seema Alam
- Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Mara Cananzi
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER),Unit of Pediatric Gastroenterology, Digestive Endoscopy, Hepatology and Care of the Child with Liver Transplantation, Department of Women’s and Children’s Health, University Hospital of Padova, Padova, Italy
| | - Noemie Laverdure
- Service de Gastroentérologie, Hépatologie et Nutrition Pédiatriques, Hospices Civils de Lyon, Hôpital Femme Mère Enfant, Lyon, France
| | | | - Felipe Ordoñez Guerrero
- Pediatric Gastroenterology and Hepatology, Fundación Cardioinfantil Instituto de Cardiologia, Bogotá, Colombia
| | - Heng Wang
- DDC Clinic - Center for Special Needs Children, Adolescent Medicine and Pediatrics, Middlefield, OH, USA
| | - Valerie Sency
- DDC Clinic - Center for Special Needs Children, Adolescent Medicine and Pediatrics, Middlefield, OH, USA
| | - Kyung Mo Kim
- Department of Pediatrics, Asan Medical Center Children's Hospital, Seoul, South Korea
| | - Huey-Ling Chen
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, National Taiwan University Children's Hospital, Taipei, Taiwan
| | - Elisa de Carvalho
- Pediatric Gastroenterology and Hepatology, Brasília Children's Hospital, Brasilia, Brazil
| | - Alexandre Fabre
- INSERM, MMG, Aix Marseille University, Marseille, France,Service de Pédiatrie Multidisciplinaire, Timone Enfant, Marseille, France
| | - Jesus Quintero Bernabeu
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER),Pediatric Hepatology and Liver Transplant Unit, Hospital Universitari Vall d'Hebron, Barcelona, Spain
| | - Aglaia Zellos
- First Department of Pediatrics, Aghia Sophia Children’s Hospital, National and Kapodistrian University of Athens, Greece
| | - Estella M. Alonso
- Childhood Liver Disease Research Network (ChiLDReN),Division of Pediatric Gastroenterology, Hepatology and Nutrition, Ann & Robert H. Lurie Children's Hospital, Chicago, IL, USA
| | - Ronald J. Sokol
- Childhood Liver Disease Research Network (ChiLDReN),Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, USA
| | - Frederick J. Suchy
- Childhood Liver Disease Research Network (ChiLDReN),Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, USA
| | - Kathleen M. Loomes
- Childhood Liver Disease Research Network (ChiLDReN),Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Patrick J. McKiernan
- Childhood Liver Disease Research Network (ChiLDReN),Department of Pediatric Gastroenterology and Hepatology, University of Pittsburgh Medical Center Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Philip Rosenthal
- Childhood Liver Disease Research Network (ChiLDReN),Department of Pediatrics and Surgery, UCSF Benioff Children's Hospital, University of California San Francisco School of Medicine, San Francisco, CA, USA
| | - Yumirle Turmelle
- Childhood Liver Disease Research Network (ChiLDReN),Section of Hepatology, Department of Pediatrics, St. Louis Children's Hospital, Washington University School of Medicine, St. Louis, MO, USA
| | - Simon Horslen
- Childhood Liver Disease Research Network (ChiLDReN),Department of Pediatric Gastroenterology and Hepatology, University of Pittsburgh Medical Center Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Kathleen Schwarz
- Childhood Liver Disease Research Network (ChiLDReN),Division of Pediatric Gastroenterology, University of California San Diego, Rady Children's Hospital San Diego, CA, USA
| | - Jorge A. Bezerra
- Childhood Liver Disease Research Network (ChiLDReN),Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Kasper Wang
- Childhood Liver Disease Research Network (ChiLDReN),Division of General Pediatric Surgery, Children's Hospital Los Angeles, Los Angeles, CA, USA
| | - Bettina E. Hansen
- Toronto Center for Liver Disease, University Health Network, Toronto, Canada,IHPME, University of Toronto, Toronto, Canada,Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Henkjan J. Verkade
- Pediatric Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, the Netherlands,European Reference Network on Hepatological Diseases (ERN RARE-LIVER),Corresponding author. Address: Pediatric Gastroenterology & Hepatology, Department of Pediatrics, Beatrix Children’s Hospital, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB Groningen, the Netherlands. Tel.: +31 50 3614147, fax: +31 50 361 1704
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10
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Abstract
Cholestatic jaundice is a common presenting feature of hepatobiliary and/or metabolic dysfunction in the newborn and young infant. Timely detection of cholestasis, followed by rapid step-wise evaluation to determine the etiology, is crucial to identify those causes that are amenable to medical or surgical intervention and to optimize outcomes for all infants. In the past 2 decades, genetic etiologies have been elucidated for many cholestatic diseases, and next-generation sequencing, whole-exome sequencing, and whole-genome sequencing now allow for relatively rapid and cost-effective diagnosis of conditions not previously identifiable via standard blood tests and/or liver biopsy. Advances have also been made in our understanding of risk factors for parenteral nutrition-associated cholestasis/liver disease. New lipid emulsion formulations, coupled with preventive measures to decrease central line-associated bloodstream infections, have resulted in lower rates of cholestasis and liver disease in infants and children receiving long-term parental nutrition. Unfortunately, little progress has been made in determining the exact cause of biliary atresia. The median age at the time of the hepatoportoenterostomy procedure is still greater than 60 days; consequently, biliary atresia remains the primary indication for pediatric liver transplantation. Several emerging therapies may reduce the bile acid load to the liver and improve outcomes in some neonatal cholestatic disorders. The goal of this article is to review the etiologies, diagnostic algorithms, and current and future management strategies for infants with cholestasis.
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Affiliation(s)
- Amy G Feldman
- Digestive Health Institute, Children's Hospital Colorado, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, CO
| | - Ronald J Sokol
- Digestive Health Institute, Children's Hospital Colorado, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, CO
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11
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Nakajima Y, Osaka S, Mizuno T, Yokoi K, Nakano S, Hirai S, Hiraoka Y, Miura Y, Suzuki M, Kusuhara H, Hayashi H. Influence of food on pharmacokinetics and pharmacodynamics of 4-phenylbutyrate in patients with urea cycle disorders. Mol Genet Metab Rep 2021; 29:100799. [PMID: 34522617 PMCID: PMC8424592 DOI: 10.1016/j.ymgmr.2021.100799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Revised: 08/28/2021] [Accepted: 08/29/2021] [Indexed: 11/19/2022] Open
Abstract
Urea cycle disorders (UCDs), inborn errors of hepatocyte metabolism, cause hyperammonemia and lead to neurocognitive deficits, coma, and even death. Sodium 4-phenylbutyrate (NaPB), a standard adjunctive therapy for UCDs, generates an alternative pathway of nitrogen deposition through glutamine consumption. Administration during or immediately after a meal is the approved usage of NaPB. However, we previously found that preprandial oral administration enhanced its potency in healthy adults and pediatric patients with intrahepatic cholestasis. The present study evaluated the effect of food on the pharmacokinetics and pharmacodynamics of NaPB in five patients with UCDs. Following an overnight fast, NaPB was administered orally at 75 mg/kg/dose (high dose, HD) or 25 mg/kg/dose (low dose, LD) either 15 min before or immediately after breakfast. Each patient was treated with these four treatment regimens with NaPB. With either dose, pre-breakfast administration rather than post-breakfast administration significantly increased plasma PB levels and decreased plasma glutamine availability. Pre-breakfast LD administration resulted in a greater attenuation in plasma glutamine availability than post-breakfast HD administration. Plasma levels of branched-chain amino acids decreased to the same extent in all tested regimens. No severe adverse events occurred during this study. In conclusion, preprandial oral administration of NaPB maximized systemic exposure of PB and thereby its efficacy on glutamine consumption in patients with UCDs.
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Key Words
- AAs, amino acids
- AUC0–4, area under the plasma concentration–time curve from time 0 to 4 h
- Amino acids
- BCAA, branched-chain amino acids
- CI, confidence interval
- Clinical study
- Cmax, the maximum plasma concentration
- HD, high dose
- Kel, elimination rate constant
- LD, low dose
- NaPB, sodium 4-phenylbutyrate
- PA, 4-phenylacetate
- PAG, 4-phenylacetylglutamine
- PB, 4-phenylbutyrate
- PD, pharmacodynamics
- PFIC, progressive familial intrahepatic cholestasis
- PK, pharmacokinetics
- Pharmacokinetics
- SD, standard deviation
- Tmax, time to reach Cmax
- UCDs, urea cycle disorders.
- Urea cycle disorders
- iAUC0–4, incremental area under the curve from time 0 to 4 h after breakfast
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Affiliation(s)
- Yoko Nakajima
- Department of Pediatrics, Fujita Health University School of Medicine, Toyoake, Japan
| | - Shuhei Osaka
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Science, The University of Tokyo, Japan
| | - Tadahaya Mizuno
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Science, The University of Tokyo, Japan
| | - Katsuyuki Yokoi
- Department of Pediatrics, Fujita Health University School of Medicine, Toyoake, Japan
| | - Satoshi Nakano
- Department of Pediatrics, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Saeko Hirai
- Department of Pediatrics, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Yuka Hiraoka
- Laboratory of Proteomics and Biomolecular Science, Research Support Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Yoshiki Miura
- Laboratory of Proteomics and Biomolecular Science, Research Support Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Mitsuyoshi Suzuki
- Department of Pediatrics, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Hiroyuki Kusuhara
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Science, The University of Tokyo, Japan
| | - Hisamitsu Hayashi
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Science, The University of Tokyo, Japan
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12
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Felzen A, Verkade HJ. The spectrum of Progressive Familial Intrahepatic Cholestasis diseases: Update on pathophysiology and emerging treatments. Eur J Med Genet 2021; 64:104317. [PMID: 34478903 DOI: 10.1016/j.ejmg.2021.104317] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 08/11/2021] [Accepted: 08/22/2021] [Indexed: 02/07/2023]
Abstract
The Progressive Familial Intrahepatic Cholestasis (PFIC) disease spectrum encompasses a variety of genetic diseases that affect the bile production and the secretion of bile acids. Typically, the first presentation of these diseases is in early childhood, frequently followed by a severe course necessitating liver transplantation before adulthood. Except for transplantation, treatment modalities have been rather limited and frequently only aim at the symptoms of cholestasis, such as cholestatic pruritus. In recent years, progress has been made in understanding the pathophysiology of these diseases and new treatment modalities have been emerging. Herewith we summarize the latest developments in the field and formulate the current key questions and opportunities for further progress.
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Affiliation(s)
- Antonia Felzen
- Pediatric Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, the Netherlands
| | - Henkjan J Verkade
- Pediatric Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, the Netherlands.
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13
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Hepatic bile acid transport increases in the postprandial state: A functional 11C-CSar PET/CT study in healthy humans. JHEP Rep 2021; 3:100288. [PMID: 34095797 PMCID: PMC8165435 DOI: 10.1016/j.jhepr.2021.100288] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 03/21/2021] [Accepted: 03/24/2021] [Indexed: 12/22/2022] Open
Abstract
Background & Aims It is not known how hepatic bile acids transport kinetics changes postprandially in the intact liver. We used positron emission tomography (PET)/computed tomography (CT) with the tracer [N-methyl-11C]cholylsarcosine (11C-CSar), a synthetic sarcosine conjugate of cholic acid, to quantify fasting and postprandial hepatic bile acid transport kinetics in healthy human participants. Methods Six healthy human participants underwent dynamic liver 11C-CSar PET/CT (60 min) during fasting and from 15 min after ingestion of a standard liquid meal. Hepatobiliary secretion kinetics of 11C-CSar was calculated from PET data, blood samples (arterial and hepatic venous) and hepatic blood flow measured using indocyanine green infusion. Results In the postprandial state, hepatic blood perfusion increased on average by 30% (p <0.01), and the flow-independent hepatic intrinsic clearance of 11C-CSar from blood into bile increased by 17% from 1.82 (range, 1.59–2.05) to 2.13 (range, 1.75–2.50) ml blood/min/ml liver tissue (p = 0.042). The increased intrinsic clearance of 11C-CSar was not caused by changes in the basolateral clearance efficacy of 11C-CSar but rather by an upregulated apical transport, as shown by an increase in the rate constant for apical secretion of 11C-CSar from hepatocyte to bile from 0.40 (0.25–0.54) min−1 to 0.67 (0.36–0.98) min−1 (p = 0.03). This resulted in a 33% increase in the intrahepatic bile flow (p = 0.03). Conclusions The rate constant for the transport of bile acids from hepatocytes into biliary canaliculi and the bile flow increased significantly in the postprandial state. This reduced the mean 11C-CSar residence time in the hepatocytes. Lay summary Bile acids are important for digestion of dietary lipids including vitamins. We examined how the secretion of bile acids by the liver into the intestines changes after a standard liquid meal. The transport of bile acids from liver cells into bile and bile flow was increased after the meal.
Following a meal, the active transport of bile acids from hepatocytes into bile is increased significantly. A meal also increases bile flow out of the liver. The postprandial changes are induced shortly after intake of a meal.
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14
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Osaka S, Nakano S, Mizuno T, Hiraoka Y, Minowa K, Hirai S, Mizutani A, Sabu Y, Miura Y, Shimizu T, Kusuhara H, Suzuki M, Hayashi H. A randomized trial to examine the impact of food on pharmacokinetics of 4-phenylbutyrate and change in amino acid availability after a single oral administration of sodium 4-phenylbutyrarte in healthy volunteers. Mol Genet Metab 2021; 132:220-226. [PMID: 33648834 DOI: 10.1016/j.ymgme.2021.02.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 02/01/2021] [Accepted: 02/01/2021] [Indexed: 12/18/2022]
Abstract
Urea cycle disorders (UCDs), inborn errors of hepatocyte metabolism, result in the systemic accumulation of ammonia to toxic levels. Sodium 4-phenylbutyrate (NaPB), a standard therapy for UCDs for over 20 years, generates an alternative pathway of nitrogen deposition through glutamine consumption. Administration during or immediately after a meal is the accepted use of NaPB. However, this regimen is not based on clinical evidence. Here, an open-label, single-dose, five-period crossover study was conducted in healthy adults to investigate the effect of food on the pharmacokinetics of NaPB and determine any subsequent change in amino acid availability. Twenty subjects were randomized to one of four treatment groups. Following an overnight fast, NaPB was administered orally at 4.3 g/m2 (high dose, HD) or 1.4 g/m2 (low dose, LD) either 30 min before or just after breakfast. At both doses, compared with post-breakfast administration, pre-breakfast administration significantly increased systemic exposure of PB and decreased plasma glutamine availability. Pre-breakfast LD administration attenuated plasma glutamine availability to the same extent as post-breakfast HD administration. Regardless of the regimen, plasma levels of branched-chain amino acids (BCAA) were decreased below baseline in a dose-dependent manner. In conclusion, preprandial oral administration of NaPB maximized systemic exposure of the drug and thereby its potency to consume plasma glutamine. This finding may improve poor medication compliance because of the issues with odor, taste, and pill burden of NaPB and reduce the risk of BCAA deficiency in NaPB therapy.
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Affiliation(s)
- Shuhei Osaka
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Science, The University of Tokyo, Japan
| | - Satoshi Nakano
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Science, The University of Tokyo, Japan; Department of Pediatrics, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Tadahaya Mizuno
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Science, The University of Tokyo, Japan
| | - Yuka Hiraoka
- Laboratory of Proteomics and Biomolecular Science, Research Support Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Kei Minowa
- Department of Pediatrics, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Saeko Hirai
- Department of Pediatrics, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Ayumu Mizutani
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Science, The University of Tokyo, Japan
| | - Yusuke Sabu
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Science, The University of Tokyo, Japan
| | - Yoshiki Miura
- Laboratory of Proteomics and Biomolecular Science, Research Support Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Toshiaki Shimizu
- Department of Pediatrics, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Hiroyuki Kusuhara
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Science, The University of Tokyo, Japan
| | - Mitsuyoshi Suzuki
- Department of Pediatrics, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Hisamitsu Hayashi
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Science, The University of Tokyo, Japan.
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15
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Amzal R, Thébaut A, Lapalus M, Almes M, Grosse B, Mareux E, Collado-Hilly M, Davit-Spraul A, Bidou L, Namy O, Jacquemin E, Gonzales E. Pharmacological Premature Termination Codon Readthrough of ABCB11 in Bile Salt Export Pump Deficiency: An In Vitro Study. Hepatology 2021; 73:1449-1463. [PMID: 32702170 DOI: 10.1002/hep.31476] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Revised: 05/22/2020] [Accepted: 06/15/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS Progressive familial intrahepatic cholestasis type 2 (PFIC2) is a severe hepatocellular cholestasis due to biallelic mutations in ABCB11 encoding the canalicular bile salt export pump (BSEP). Nonsense mutations are responsible for the most severe phenotypes. The aim was to assess the ability of drugs to induce readthrough of six nonsense mutations (p.Y354X, p.R415X, p.R470X, p.R1057X, p.R1090X, and p.E1302X) identified in patients with PFIC2. APPROACH AND RESULTS The ability of G418, gentamicin, and PTC124 to induce readthrough was studied using a dual gene reporter system in NIH3T3 cells. The ability of gentamicin to induce readthrough and to lead to the expression of a full-length protein was studied in human embryonic kidney 293 (HEK293), HepG2, and Can 10 cells using immunodetection assays. The function of the gentamicin-induced full-length protein was studied by measuring the [3 H]-taurocholate transcellular transport in stable Madin-Darby canine kidney clones co-expressing Na+-taurocholate co-transporting polypeptide (Ntcp). Combinations of gentamicin and chaperone drugs (ursodeoxycholic acid, 4-phenylbutyrate [4-PB]) were investigated. In NIH3T3, aminoglycosides significantly increased the readthrough level of all mutations studied, while PTC124 only slightly increased the readthrough of p.E1302X. Gentamicin induced a readthrough of p.R415X, p.R470X, p.R1057X, and p.R1090X in HEK293 cells. The resulting full-length proteins localized within the cytoplasm, except for BsepR1090X , which was also detected at the plasma membrane of human embryonic kidney HEK293 and at the canalicular membrane of Can 10 and HepG2 cells. Additional treatment with 4-PB and ursodeoxycholic acid significantly increased the canalicular proportion of full-length BsepR1090X protein in Can 10 cells. In Madin-Darby canine kidney clones, gentamicin induced a 40% increase of the BsepR1090X [3 H]-taurocholate transport, which was further increased with additional 4-PB treatment. CONCLUSION This study constitutes a proof of concept for readthrough therapy in selected patients with PFIC2 with nonsense mutations.
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Affiliation(s)
- Rachida Amzal
- Université Paris-Saclay, Inserm, Physiopathogénèse et traitement des maladies du Foie, UMR_S 1193, Hepatinov, Orsay, France
| | - Alice Thébaut
- Université Paris-Saclay, Inserm, Physiopathogénèse et traitement des maladies du Foie, UMR_S 1193, Hepatinov, Orsay, France
- Pediatric Hepatology & Pediatric Liver Transplant Department, Centre de Référence de l'Atrésie des Voies Biliaires et des Cholestases Génétiques, Filière de Santé des Maladies Rares du Foie de l'enfant et de l'adulte, European Reference Network RARE-LIVER, Assistance Publique-Hôpitaux de Paris, Faculty of Medecine Paris-Saclay, CHU Bicêtre, Le Kremlin-Bicêtre, France
| | - Martine Lapalus
- Université Paris-Saclay, Inserm, Physiopathogénèse et traitement des maladies du Foie, UMR_S 1193, Hepatinov, Orsay, France
| | - Marion Almes
- Université Paris-Saclay, Inserm, Physiopathogénèse et traitement des maladies du Foie, UMR_S 1193, Hepatinov, Orsay, France
- Pediatric Hepatology & Pediatric Liver Transplant Department, Centre de Référence de l'Atrésie des Voies Biliaires et des Cholestases Génétiques, Filière de Santé des Maladies Rares du Foie de l'enfant et de l'adulte, European Reference Network RARE-LIVER, Assistance Publique-Hôpitaux de Paris, Faculty of Medecine Paris-Saclay, CHU Bicêtre, Le Kremlin-Bicêtre, France
| | - Brigitte Grosse
- Université Paris-Saclay, Inserm, Physiopathogénèse et traitement des maladies du Foie, UMR_S 1193, Hepatinov, Orsay, France
| | - Elodie Mareux
- Université Paris-Saclay, Inserm, Physiopathogénèse et traitement des maladies du Foie, UMR_S 1193, Hepatinov, Orsay, France
| | - Mauricette Collado-Hilly
- Université Paris-Saclay, Inserm, Physiopathogénèse et traitement des maladies du Foie, UMR_S 1193, Hepatinov, Orsay, France
| | - Anne Davit-Spraul
- Université Paris-Saclay, Inserm, Physiopathogénèse et traitement des maladies du Foie, UMR_S 1193, Hepatinov, Orsay, France
- Biochemistry Unit, Assistance Publique-Hôpitaux de Paris, CHU Bicêtre, Le Kremlin-Bicêtre, France
| | - Laure Bidou
- Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Université Paris-Saclay, Gif sur Yvette cedex, France
- Sorbonne Universités, Université Pierre et Marie Curie, UPMC, Paris, France
| | - Olivier Namy
- Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Université Paris-Saclay, Gif sur Yvette cedex, France
| | - Emmanuel Jacquemin
- Université Paris-Saclay, Inserm, Physiopathogénèse et traitement des maladies du Foie, UMR_S 1193, Hepatinov, Orsay, France
- Pediatric Hepatology & Pediatric Liver Transplant Department, Centre de Référence de l'Atrésie des Voies Biliaires et des Cholestases Génétiques, Filière de Santé des Maladies Rares du Foie de l'enfant et de l'adulte, European Reference Network RARE-LIVER, Assistance Publique-Hôpitaux de Paris, Faculty of Medecine Paris-Saclay, CHU Bicêtre, Le Kremlin-Bicêtre, France
| | - Emmanuel Gonzales
- Université Paris-Saclay, Inserm, Physiopathogénèse et traitement des maladies du Foie, UMR_S 1193, Hepatinov, Orsay, France
- Pediatric Hepatology & Pediatric Liver Transplant Department, Centre de Référence de l'Atrésie des Voies Biliaires et des Cholestases Génétiques, Filière de Santé des Maladies Rares du Foie de l'enfant et de l'adulte, European Reference Network RARE-LIVER, Assistance Publique-Hôpitaux de Paris, Faculty of Medecine Paris-Saclay, CHU Bicêtre, Le Kremlin-Bicêtre, France
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16
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Medically Important Alterations in Transport Function and Trafficking of ABCG2. Int J Mol Sci 2021; 22:ijms22062786. [PMID: 33801813 PMCID: PMC8001156 DOI: 10.3390/ijms22062786] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 03/04/2021] [Accepted: 03/05/2021] [Indexed: 02/06/2023] Open
Abstract
Several polymorphisms and mutations in the human ABCG2 multidrug transporter result in reduced plasma membrane expression and/or diminished transport function. Since ABCG2 plays a pivotal role in uric acid clearance, its malfunction may lead to hyperuricemia and gout. On the other hand, ABCG2 residing in various barrier tissues is involved in the innate defense mechanisms of the body; thus, genetic alterations in ABCG2 may modify the absorption, distribution, excretion of potentially toxic endo- and exogenous substances. In turn, this can lead either to altered therapy responses or to drug-related toxic reactions. This paper reviews the various types of mutations and polymorphisms in ABCG2, as well as the ways how altered cellular processing, trafficking, and transport activity of the protein can contribute to phenotypic manifestations. In addition, the various methods used for the identification of the impairments in ABCG2 variants and the different approaches to correct these defects are overviewed.
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17
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Wu SH, Chang MH, Chen YH, Wu HL, Chua HH, Chien CS, Ni YH, Chen HL, Chen HL. The ESCRT-III molecules regulate the apical targeting of bile salt export pump. J Biomed Sci 2021; 28:19. [PMID: 33750401 PMCID: PMC7941988 DOI: 10.1186/s12929-020-00706-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 12/30/2020] [Indexed: 11/17/2022] Open
Abstract
Background The bile salt export pump (BSEP) is a pivotal apical/canalicular bile salt transporter in hepatocytes that drives the bile flow. Defects in BSEP function and canalicular expression could lead to a spectrum of cholestatic liver diseases. One prominent manifestation of BSEP-associated cholestasis is the defective canalicular localization and cytoplasmic retention of BSEP. However, the etiology of impaired BSEP targeting to the canalicular membrane is not fully understood. Our goal was to discover what molecule could interact with BSEP and affect its post-Golgi sorting. Methods The human BSEP amino acids (a.a.) 491-630 was used as bait to screen a human fetal liver cDNA library through yeast two-hybrid system. We identified a BSEP-interacting candidate and showed the interaction and colocalization in the co-immunoprecipitation in hepatoma cell lines and histological staining in human liver samples. Temperature shift assays were used to study the post-Golgi trafficking of BSEP. We further determine the functional impacts of the BSEP-interacting candidate on BSEP in vitro. A hydrodynamically injected mouse model was established for in vivo characterizing the long-term impacts on BSEP. Results We identified that charged multivesicular body protein 5 (CHMP5), a molecule of the endosomal protein complex required for transport subcomplex-III (ESCRT-III), interacted and co-localized with BSEP in the subapical compartments (SACs) in developing human livers. Cholestatic BSEP mutations in the CHMP5-interaction region have defects in canalicular targeting and aberrant retention at the SACs. Post-Golgi delivery of BSEP and bile acid secretion were impaired in ESCRT-III perturbation or CHMP5-knockdown hepatic cellular and mouse models. This ESCRT-III-mediated BSEP sorting preceded Rab11A-regulated apical cycling of BSEP. Conclusions Our results showed the first example that ESCRT-III is essential for canalicular trafficking of apical membrane proteins, and provide new targets for therapeutic approaches in BSEP associated cholestasis.
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Affiliation(s)
- Shang-Hsin Wu
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, 100, Taiwan
| | - Mei-Hwei Chang
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, 100, Taiwan.,Department of Pediatrics, National Taiwan University College of Medicine and National Taiwan University Children's Hospital, Taipei, 100, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, Taipei, 100, Taiwan
| | - Ya-Hui Chen
- Department of Pediatrics, National Taiwan University College of Medicine and National Taiwan University Children's Hospital, Taipei, 100, Taiwan
| | - Hui-Lin Wu
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, 100, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, Taipei, 100, Taiwan
| | - Huey-Huey Chua
- Department of Pediatrics, National Taiwan University College of Medicine and National Taiwan University Children's Hospital, Taipei, 100, Taiwan
| | - Chin-Sung Chien
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, 100, Taiwan
| | - Yen-Hsuan Ni
- Department of Pediatrics, National Taiwan University College of Medicine and National Taiwan University Children's Hospital, Taipei, 100, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, Taipei, 100, Taiwan.,Medical Microbiota Center of the First Core Laboratory, National Taiwan University College of Medicine, Taipei, 100, Taiwan
| | - Hui-Ling Chen
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, 100, Taiwan.
| | - Huey-Ling Chen
- Department of Pediatrics, National Taiwan University College of Medicine and National Taiwan University Children's Hospital, Taipei, 100, Taiwan. .,Hepatitis Research Center, National Taiwan University Hospital, Taipei, 100, Taiwan. .,Department and Graduate Institute of Medical Education and Bioethics, National Taiwan University College of Medicine, Taipei, 100, Taiwan.
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18
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Molecular Regulation of Canalicular ABC Transporters. Int J Mol Sci 2021; 22:ijms22042113. [PMID: 33672718 PMCID: PMC7924332 DOI: 10.3390/ijms22042113] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 02/15/2021] [Accepted: 02/18/2021] [Indexed: 12/17/2022] Open
Abstract
The ATP-binding cassette (ABC) transporters expressed at the canalicular membrane of hepatocytes mediate the secretion of several compounds into the bile canaliculi and therefore play a key role in bile secretion. Among these transporters, ABCB11 secretes bile acids, ABCB4 translocates phosphatidylcholine and ABCG5/G8 is responsible for cholesterol secretion, while ABCB1 and ABCC2 transport a variety of drugs and other compounds. The dysfunction of these transporters leads to severe, rare, evolutionary biliary diseases. The development of new therapies for patients with these diseases requires a deep understanding of the biology of these transporters. In this review, we report the current knowledge regarding the regulation of canalicular ABC transporters' folding, trafficking, membrane stability and function, and we highlight the role of molecular partners in these regulating mechanisms.
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19
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Bartos Z, Homolya L. Identification of Specific Trafficking Defects of Naturally Occurring Variants of the Human ABCG2 Transporter. Front Cell Dev Biol 2021; 9:615729. [PMID: 33634118 PMCID: PMC7900420 DOI: 10.3389/fcell.2021.615729] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 01/05/2021] [Indexed: 01/04/2023] Open
Abstract
Proper targeting of the urate and xenobiotic transporter ATP-binding transporter subfamily G member 2 (ABCG2) to the plasma membrane (PM) is essential for its normal function. The naturally occurring Q141K and M71V polymorphisms in ABCG2, associated with gout and hyperuricemia, affect the cellular routing of the transporter, rather than its transport function. The cellular localization of ABCG2 variants was formerly studied by immunolabeling, which provides information only on the steady-state distribution of the protein, leaving the dynamics of its cellular routing unexplored. In the present study, we assessed in detail the trafficking of the wild-type, M71V-, and Q141K-ABCG2 variants from the endoplasmic reticulum (ER) to the cell surface using a dynamic approach, the so-called Retention Using Selective Hooks (RUSH) system. This method also allowed us to study the kinetics of glycosylation of these variants. We found that the fraction of Q141K- and M71V-ABCG2 that passes the ER quality control system is only partially targeted to the PM; a subfraction is immobile and retained in the ER. Surprisingly, the transit of these variants through the Golgi apparatus (either the appearance or the exit) was unaffected; however, their PM delivery beyond the Golgi was delayed. In addition to identifying the specific defects in the trafficking of these ABCG2 variants, our study provides a novel experimental tool for studying the effect of drugs that potentially promote the cell surface delivery of mutant or polymorphic ABCG2 variants with impaired trafficking.
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Affiliation(s)
- Zsuzsa Bartos
- Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences Centre of Excellence, Budapest, Hungary
| | - László Homolya
- Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences Centre of Excellence, Budapest, Hungary
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20
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Sohail MI, Dönmez-Cakil Y, Szöllősi D, Stockner T, Chiba P. The Bile Salt Export Pump: Molecular Structure, Study Models and Small-Molecule Drugs for the Treatment of Inherited BSEP Deficiencies. Int J Mol Sci 2021; 22:E784. [PMID: 33466755 PMCID: PMC7830293 DOI: 10.3390/ijms22020784] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 01/11/2021] [Accepted: 01/12/2021] [Indexed: 02/07/2023] Open
Abstract
The bile salt export pump (BSEP/ABCB11) is responsible for the transport of bile salts from hepatocytes into bile canaliculi. Malfunction of this transporter results in progressive familial intrahepatic cholestasis type 2 (PFIC2), benign recurrent intrahepatic cholestasis type 2 (BRIC2) and intrahepatic cholestasis of pregnancy (ICP). Over the past few years, several small molecular weight compounds have been identified, which hold the potential to treat these genetic diseases (chaperones and potentiators). As the treatment response is mutation-specific, genetic analysis of the patients and their families is required. Furthermore, some of the mutations are refractory to therapy, with the only remaining treatment option being liver transplantation. In this review, we will focus on the molecular structure of ABCB11, reported mutations involved in cholestasis and current treatment options for inherited BSEP deficiencies.
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Affiliation(s)
| | - Yaprak Dönmez-Cakil
- Department of Histology and Embryology, Faculty of Medicine, Maltepe University, Maltepe, 34857 Istanbul, Turkey;
| | - Dániel Szöllősi
- Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Waehringerstrasse, 13A, 1090 Vienna, Austria;
| | - Thomas Stockner
- Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Waehringerstrasse, 13A, 1090 Vienna, Austria;
| | - Peter Chiba
- Institute of Medical Chemistry, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Waehringerstrasse, 10, 1090 Vienna, Austria
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21
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Amirneni S, Haep N, Gad MA, Soto-Gutierrez A, Squires JE, Florentino RM. Molecular overview of progressive familial intrahepatic cholestasis. World J Gastroenterol 2020; 26:7470-7484. [PMID: 33384548 PMCID: PMC7754551 DOI: 10.3748/wjg.v26.i47.7470] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 11/05/2020] [Accepted: 11/29/2020] [Indexed: 02/06/2023] Open
Abstract
Cholestasis is a clinical condition resulting from the imapairment of bile flow. This condition could be caused by defects of the hepatocytes, which are responsible for the complex process of bile formation and secretion, and/or caused by defects in the secretory machinery of cholangiocytes. Several mutations and pathways that lead to cholestasis have been described. Progressive familial intrahepatic cholestasis (PFIC) is a group of rare diseases caused by autosomal recessive mutations in the genes that encode proteins expressed mainly in the apical membrane of the hepatocytes. PFIC 1, also known as Byler’s disease, is caused by mutations of the ATP8B1 gene, which encodes the familial intrahepatic cholestasis 1 protein. PFIC 2 is characterized by the downregulation or absence of functional bile salt export pump (BSEP) expression via variations in the ABCB11 gene. Mutations of the ABCB4 gene result in lower expression of the multidrug resistance class 3 glycoprotein, leading to the third type of PFIC. Newer variations of this disease have been described. Loss of function of the tight junction protein 2 protein results in PFIC 4, while mutations of the NR1H4 gene, which encodes farnesoid X receptor, an important transcription factor for bile formation, cause PFIC 5. A recently described type of PFIC is associated with a mutation in the MYO5B gene, important for the trafficking of BSEP and hepatocyte membrane polarization. In this review, we provide a brief overview of the molecular mechanisms and clinical features associated with each type of PFIC based on peer reviewed journals published between 1993 and 2020.
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Affiliation(s)
- Sriram Amirneni
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, United States
| | - Nils Haep
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, United States
| | - Mohammad A Gad
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, United States
| | - Alejandro Soto-Gutierrez
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, United States
- Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15213, United States
| | - James E Squires
- Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15213, United States
- Division of Gastroenterology, Hepatology, and Nutrition, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, United States
| | - Rodrigo M Florentino
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, United States
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22
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Lee W, Ha JM, Sugiyama Y. Post-translational regulation of the major drug transporters in the families of organic anion transporters and organic anion-transporting polypeptides. J Biol Chem 2020; 295:17349-17364. [PMID: 33051208 PMCID: PMC7863896 DOI: 10.1074/jbc.rev120.009132] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Revised: 10/13/2020] [Indexed: 12/16/2022] Open
Abstract
The organic anion transporters (OATs) and organic anion-transporting polypeptides (OATPs) belong to the solute carrier (SLC) transporter superfamily and play important roles in handling various endogenous and exogenous compounds of anionic charge. The OATs and OATPs are often implicated in drug therapy by impacting the pharmacokinetics of clinically important drugs and, thereby, drug exposure in the target organs or cells. Various mechanisms (e.g. genetic, environmental, and disease-related factors, drug-drug interactions, and food-drug interactions) can lead to variations in the expression and activity of the anion drug-transporting proteins of OATs and OATPs, possibly impacting the therapeutic outcomes. Previous investigations mainly focused on the regulation at the transcriptional level and drug-drug interactions as competing substrates or inhibitors. Recently, evidence has accumulated that cellular trafficking, post-translational modification, and degradation mechanisms serve as another important layer for the mechanisms underlying the variations in the OATs and OATPs. This review will provide a brief overview of the major OATs and OATPs implicated in drug therapy and summarize recent progress in our understanding of the post-translational modifications, in particular ubiquitination and degradation pathways of the individual OATs and OATPs implicated in drug therapy.
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Affiliation(s)
- Wooin Lee
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea.
| | - Jeong-Min Ha
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea
| | - Yuichi Sugiyama
- Sugiyama Laboratory, RIKEN Cluster for Science, Technology and Innovation Hub, Yokohama, Kanagawa, Japan
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23
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Kroll T, Prescher M, Smits SHJ, Schmitt L. Structure and Function of Hepatobiliary ATP Binding Cassette Transporters. Chem Rev 2020; 121:5240-5288. [PMID: 33201677 DOI: 10.1021/acs.chemrev.0c00659] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The liver is beyond any doubt the most important metabolic organ of the human body. This function requires an intensive crosstalk within liver cellular structures, but also with other organs. Membrane transport proteins are therefore of upmost importance as they represent the sensors and mediators that shuttle signals from outside to the inside of liver cells and/or vice versa. In this review, we summarize the known literature of liver transport proteins with a clear emphasis on functional and structural information on ATP binding cassette (ABC) transporters, which are expressed in the human liver. These primary active membrane transporters form one of the largest families of membrane proteins. In the liver, they play an essential role in for example bile formation or xenobiotic export. Our review provides a state of the art and comprehensive summary of the current knowledge of hepatobiliary ABC transporters. Clearly, our knowledge has improved with a breath-taking speed over the last few years and will expand further. Thus, this review will provide the status quo and will lay the foundation for new and exciting avenues in liver membrane transporter research.
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Affiliation(s)
- Tim Kroll
- Institute of Biochemistry, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany
| | - Martin Prescher
- Institute of Biochemistry, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany
| | - Sander H J Smits
- Institute of Biochemistry, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany.,Center for Structural Studies, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany
| | - Lutz Schmitt
- Institute of Biochemistry, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany
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24
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Sarkadi B, Homolya L, Hegedűs T. The ABCG2/BCRP transporter and its variants - from structure to pathology. FEBS Lett 2020; 594:4012-4034. [PMID: 33015850 DOI: 10.1002/1873-3468.13947] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 08/27/2020] [Accepted: 09/21/2020] [Indexed: 12/13/2022]
Abstract
The ABCG2 protein has a key role in the transport of a wide range of structurally dissimilar endo- and xenobiotics in the human body, especially in the tissue barriers and the metabolizing or secreting organs. The human ABCG2 gene harbors a high number of polymorphisms and mutations, which may significantly modulate its expression and function. Recent high-resolution structural data, complemented with molecular dynamic simulations, may significantly help to understand intramolecular movements and substrate handling, as well as the effects of mutations on the membrane transporter function of ABCG2. As reviewed here, structural alterations may result not only in direct alterations in drug binding and transporter activity, but also in improper folding or problems in the carefully regulated process of trafficking, including vesicular transport, endocytosis, recycling, and degradation. Here, we also review the clinical importance of altered ABCG2 expression and function in general drug metabolism, cancer multidrug resistance, and impaired uric acid excretion, leading to gout.
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Affiliation(s)
- Balázs Sarkadi
- Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary.,Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary
| | - László Homolya
- Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary
| | - Tamás Hegedűs
- Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary
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25
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Brecker M, Khakhina S, Schubert TJ, Thompson Z, Rubenstein RC. The Probable, Possible, and Novel Functions of ERp29. Front Physiol 2020; 11:574339. [PMID: 33013490 PMCID: PMC7506106 DOI: 10.3389/fphys.2020.574339] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Accepted: 08/14/2020] [Indexed: 12/16/2022] Open
Abstract
The luminal endoplasmic reticulum (ER) protein of 29 kDa (ERp29) is a ubiquitously expressed cellular agent with multiple critical roles. ERp29 regulates the biosynthesis and trafficking of several transmembrane and secretory proteins, including the cystic fibrosis transmembrane conductance regulator (CFTR), the epithelial sodium channel (ENaC), thyroglobulin, connexin 43 hemichannels, and proinsulin. ERp29 is hypothesized to promote ER to cis-Golgi cargo protein transport via COP II machinery through its interactions with the KDEL receptor; this interaction may facilitate the loading of ERp29 clients into COP II vesicles. ERp29 also plays a role in ER stress (ERS) and the unfolded protein response (UPR) and is implicated in oncogenesis. Here, we review the vast array of ERp29’s clients, its role as an ER to Golgi escort protein, and further suggest ERp29 as a potential target for therapies related to diseases of protein misfolding and mistrafficking.
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Affiliation(s)
- Margaret Brecker
- Cystic Fibrosis Center, The Children’s Hospital of Philadelphia, Philadelphia, PA, United States
| | - Svetlana Khakhina
- Cystic Fibrosis Center, The Children’s Hospital of Philadelphia, Philadelphia, PA, United States
| | - Tyler J. Schubert
- Cystic Fibrosis Center, The Children’s Hospital of Philadelphia, Philadelphia, PA, United States
| | - Zachary Thompson
- Cystic Fibrosis Center, The Children’s Hospital of Philadelphia, Philadelphia, PA, United States
| | - Ronald C. Rubenstein
- Cystic Fibrosis Center, The Children’s Hospital of Philadelphia, Philadelphia, PA, United States
- Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States
- Division of Allergy and Pulmonary Medicine, Department of Pediatrics, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
- *Correspondence: Ronald C. Rubenstein, ;
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Braun D, Schweizer U. The Protein Translocation Defect of MCT8 L291R Is Rescued by Sodium Phenylbutyrate. Eur Thyroid J 2020; 9:269-280. [PMID: 33088796 PMCID: PMC7548921 DOI: 10.1159/000507439] [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: 12/20/2019] [Accepted: 03/24/2020] [Indexed: 11/19/2022] Open
Abstract
INTRODUCTION The monocarboxylate transporter 8 (MCT8; SLC16A2) is a specific transporter for thyroid hormones. MCT8 deficiency, formerly known as the Allan-Herndon-Dudley syndrome, is a rare genetic disease that leads to neurological impairments and muscle weakness. Current experimental treatment options rely on thyromimetic agonists that do not depend on MCT8 for cellular uptake. Another approach comes from studies with the chemical chaperone sodium phenylbutyrate (NaPB), which was able to stabilize MCT8 mutants having protein folding defects in vitro. In addition, NaPB is known as a compound that assists with plasma membrane translocation. OBJECTIVE The pathogenic MCT8L291R leads to the same severe neurological impairments found for other MCT8-deficient patients but, unexpectedly, lacks alterations in plasma 3,3',5-triiodothyronine (T3) levels. Here we tried to unravel the underlying mechanism of MCT8 deficiency and tested whether the pathogenic MCT8L291R mutant responds to NaPB treatment. Therefore, we overexpressed the mutant in Madin-Darby canine kidney cells in the human choriocarcinoma cell line JEG1 and in COS7 cells of African green monkey origin. RESULTS In our recent study we describe that the MCT8L291R mutation most likely leads to a translocation defect. The pathogenic mutant is not located at the plasma membrane, but shows overlapping expression with a marker protein of the lysosome. Mutation of the corresponding amino acid in murine Mct8 (Mct8L223R) displays a similar effect on cell surface expression and transport function as seen before for MCT8L291R. NaPB was able to correct the translocation defect of MCT8L291R/Mct8L223R and restored protein function by increasing T3 transport activity. Furthermore, we detected enhanced mRNA levels of wild-type and mutant MCT8/Mct8 after NaPB treatment. The increase in mRNA levels could be an explanation for the positive effect on protein expression and function detected for wild-type MCT8. CONCLUSION NaPB is not only suitable for the treatment of mutations leading to misfolding and protein degradation, but also for a mutant wrongly sorted inside a cell which is otherwise functional.
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Affiliation(s)
- Doreen Braun
- *Doreen Braun, Institut für Biochemie und Molekularbiologie, Medizinische Fakultät, Rheinische Friedrich-Wilhelms-Universität Bonn, Nussallee 11, DE–53115 Bonn (Germany),
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27
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Stättermayer AF, Halilbasic E, Wrba F, Ferenci P, Trauner M. Variants in ABCB4 (MDR3) across the spectrum of cholestatic liver diseases in adults. J Hepatol 2020; 73:651-663. [PMID: 32376413 DOI: 10.1016/j.jhep.2020.04.036] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 04/18/2020] [Accepted: 04/22/2020] [Indexed: 12/14/2022]
Abstract
The ATP binding cassette subfamily B member 4 (ABCB4) gene on chromosome 7 encodes the ABCB4 protein (alias multidrug resistance protein 3 [MDR3]), a P-glycoprotein in the canalicular membrane of the hepatocytes that acts as a translocator of phospholipids into bile. Several variants in ABCB4 have been shown to cause ABCB4 deficiency, accounting for a disease spectrum ranging from progressive familial cholestasis type 3 to less severe conditions like low phospholipid-associated cholelithiasis, intrahepatic cholestasis of pregnancy or drug-induced liver injury. Furthermore, whole genome sequencing has shown that ABCB4 variants are associated with an increased incidence of gallstone disease, gallbladder and bile duct carcinoma, liver cirrhosis or elevated liver function tests. Diagnosis of ABCB4 deficiency-related diseases is based on clinical presentation, serum biomarkers, imaging techniques, liver histology and genetic testing. Nevertheless, the clinical presentation can vary widely and clear genotype-phenotype correlations are currently lacking. Ursodeoxycholic acid is the most commonly used medical treatment, but its efficacy has yet to be proven in large controlled clinical studies. Future pharmacological options may include stimulation/restoration of residual function by chaperones (e.g. 4-phenyl butyric acid, curcumin) or induction of ABCB4 transcription by FXR (farnesoid X receptor) agonists or PPARα (peroxisome proliferator-activated receptor-α)-ligands/fibrates. Orthotopic liver transplantation remains the last and often only therapeutic option in cirrhotic patients with end-stage liver disease or patients with intractable pruritus.
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Affiliation(s)
- Albert Friedrich Stättermayer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Emina Halilbasic
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Fritz Wrba
- Institute of Clinical Pathology, Medical University of Vienna, Vienna, Austria
| | - Peter Ferenci
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
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Yumoto T, Kimura M, Nagatomo R, Sato T, Utsunomiya S, Aoki N, Kitaura M, Takahashi K, Takemoto H, Watanabe H, Okano H, Yoshida F, Nao Y, Tomita T. Autism-associated variants of neuroligin 4X impair synaptogenic activity by various molecular mechanisms. Mol Autism 2020; 11:68. [PMID: 32873342 PMCID: PMC7465329 DOI: 10.1186/s13229-020-00373-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Accepted: 08/20/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Several genetic alterations, including point mutations and copy number variations in NLGN genes, have been associated with psychiatric disorders, such as autism spectrum disorder (ASD) and X-linked mental retardation (XLMR). NLGN genes encode neuroligin (NL) proteins, which are adhesion molecules that are important for proper synaptic formation and maturation. Previously, we and others found that the expression level of murine NL1 is regulated by proteolytic processing in a synaptic activity-dependent manner. METHODS In this study, we analyzed the effects of missense variants associated with ASD and XLMR on the metabolism and function of NL4X, a protein which is encoded by the NLGN4X gene and is expressed only in humans, using cultured cells, primary neurons from rodents, and human induced pluripotent stem cell-derived neurons. RESULTS NL4X was found to undergo proteolytic processing in human neuronal cells. Almost all NL4X variants caused a substantial decrease in the levels of mature NL4X and its synaptogenic activity in a heterologous culture system. Intriguingly, the L593F variant of NL4X accelerated the proteolysis of mature NL4X proteins located on the cell surface. In contrast, other variants decreased the cell-surface trafficking of NL4X. Notably, protease inhibitors as well as chemical chaperones rescued the expression of mature NL4X. LIMITATIONS Our study did not reveal whether these dysfunctional phenotypes occurred in individuals carrying NLGN4X variant. Moreover, though these pathological mechanisms could be exploited as potential drug targets for ASD, it remains unclear whether these compounds would have beneficial effects on ASD model animals and patients. CONCLUSIONS These data suggest that reduced amounts of the functional NL4X protein on the cell surface is a common mechanism by which point mutants of the NL4X protein cause psychiatric disorders, although different molecular mechanisms are thought to be involved. Furthermore, these results highlight that the precision medicine approach based on genetic and cell biological analyses is important for the development of therapeutics for psychiatric disorders.
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Affiliation(s)
- Takafumi Yumoto
- Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Misaki Kimura
- Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Ryota Nagatomo
- Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Tsukika Sato
- Department of Physiology, Keio University School of Medicine, Tokyo, Japan
| | - Shun Utsunomiya
- Neuroscience 2, Laboratory for Drug Discovery and Disease Research, Shionogi, Osaka, Japan
- Business-Academia Collaborative Laboratory (Shionogi), Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo, Japan
| | - Natsue Aoki
- Neuroscience 2, Laboratory for Drug Discovery and Disease Research, Shionogi, Osaka, Japan
- Business-Academia Collaborative Laboratory (Shionogi), Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo, Japan
| | - Motoji Kitaura
- Research Administration SPRC, R&D General Administration Unit, General Administration Division, Shionogi Administration Service, Osaka, Japan
| | - Koji Takahashi
- Drug Discovery Technology 3, Laboratory for Innovative Therapy Research, Shionogi, Osaka, Japan
| | - Hiroshi Takemoto
- Neuroscience 2, Laboratory for Drug Discovery and Disease Research, Shionogi, Osaka, Japan
- Business-Academia Collaborative Laboratory (Shionogi), Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo, Japan
| | - Hirotaka Watanabe
- Department of Physiology, Keio University School of Medicine, Tokyo, Japan
| | - Hideyuki Okano
- Department of Physiology, Keio University School of Medicine, Tokyo, Japan
| | - Fumiaki Yoshida
- Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Yosuke Nao
- Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Taisuke Tomita
- Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
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Abstract
Neonatal cholestasis is characterized by conjugated hyperbilirubinemia in the newborn and young infant and is a sign common to over 100 hepatobiliary and/or metabolic disorders. A timely evaluation for its etiology is critical in order to quickly identify treatable causes such as biliary atresia, many of which benefit from early therapy. An expanding group of molecularly defined disorders involving bile formation, canalicular transporters, tight junction proteins and inborn errors of metabolism are being continuously discovered because of advances in genetic testing and bioinformatics. The advent of next generation sequencing has transformed our ability to test for multiple genes and whole exome or whole genome sequencing within days to weeks, enabling rapid and affordable molecular diagnosis for disorders that cannot be directly diagnosed from standard blood tests or liver biopsy. Thus, our diagnostic algorithms for neonatal cholestasis are undergoing transformation, moving genetic sequencing to earlier in the evaluation pathway once biliary atresia, "red flag" disorders and treatable disorders are excluded. Current therapies focus on promoting bile flow, reducing pruritus, ensuring optimal nutrition, and monitoring for complications, without addressing the underlying cause of cholestasis in most instances. Our improved understanding of bile formation and the enterohepatic circulation of bile acids has led to emerging therapies for cholestasis which require appropriate pediatric clinical trials. Despite these advances, the cause and optimal therapy for biliary atresia remain elusive. The goals of this review are to outline the etiologies, diagnostic pathways and current and emerging management strategies for neonatal cholestasis.
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Affiliation(s)
- Amy G. Feldman
- Pediatric Liver Center, Digestive Health Institute, Children’s Hospital Colorado, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Ronald J. Sokol
- Pediatric Liver Center, Digestive Health Institute, Children’s Hospital Colorado, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, Colorado, USA,Colorado Clinical and Translational Sciences Institute, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA,Corresponding Author: Ronald J. Sokol, Digestive Health Institute, Children’s Hospital Colorado, Box B290, 13123 E. 16th Ave., Aurora, Colorado, 80045, USA Phone: 720-777-6669, Fax: 720-777-7277,
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30
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Zen Y, Kondou H, Nakazawa A, Tanikawa K, Hasegawa Y, Bessho K, Imagawa K, Ishige T, Inui A, Suzuki M, Kasahara M, Yamamoto K, Yoshioka T, Kage M, Hayashi H. Proposal of a liver histology-based scoring system for bile salt export pump deficiency. Hepatol Res 2020; 50:754-762. [PMID: 32073700 DOI: 10.1111/hepr.13494] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 02/10/2020] [Accepted: 02/11/2020] [Indexed: 02/08/2023]
Abstract
AIM Bile salt export pump (BSEP) deficiency manifests a form of progressive intrahepatic cholestasis. This study aimed to establish a scoring system of liver histology for the uncommon genetic condition. METHODS After a roundtable discussion and histology review, a scoring system for BSEP deficiency was established. Eleven tissue samples were independently evaluated by three pathologists based on the proposed standard for an interobserver agreement analysis. In four cases with serial tissue samples available, correlation between changes in histology scores and clinical outcome was examined. RESULTS Of 14 initially listed histopathological findings, 12 were selected for scoring and grouped into the following four categories: cholestasis, parenchymal changes, portal tract changes and fibrosis. Each category consisted of two to four microscopic findings that were further divided into three to six scores; therefore, each category had a maximum score of 8-11. Interobserver agreement was highest for pericellular fibrosis (κ = 0.849) and lowest for hepatocellular cholestasis (κ = 0.241) with the mean and median κ values of the 12 parameters being 0.561 and 0.602, respectively. For two patients whose clinical features worsened, score changes between two time points were interpreted as deteriorated. In two patients, who showed a good clinical response to preprandial treatment with sodium 4-phenylbutyrate, histological changes were evaluated as improved or unchanged. CONCLUSIONS The proposed histology-based scoring system for BSEP deficiency with moderate interobserver agreement may be useful not only for monitoring microscopic changes in clinical practice but also for a surrogate endpoint in clinical trials.
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Affiliation(s)
- Yoh Zen
- Department of Diagnostic Pathology, Kobe University, Hyogo, Japan
| | - Hiroki Kondou
- Department of Pediatrics, Kindai University Nara Hospital, Nara, Japan
| | - Atsuko Nakazawa
- Department of Clinical Research, Saitama Children's Medical Center, Saitama, Japan
| | - Ken Tanikawa
- Department of Diagnostic Pathology, Kurume University Hospital, Fukuoka, Japan
| | - Yasuhiro Hasegawa
- Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Kazuhiko Bessho
- Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Kazuo Imagawa
- Department of Pediatrics, University of Tsukuba Hospital, Ibaraki, Japan
| | - Takashi Ishige
- Department of Pediatrics, Gunma University Graduate School of Medicine, Gunma, Japan
| | - Ayano Inui
- Department of Pediatric Hepatology and Gastroenterology, Saiseikai Yokohama City Tobu Hospital, Kanagawa, Japan
| | - Mitsuyoshi Suzuki
- Department of Pediatrics, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Mureo Kasahara
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| | - Kouji Yamamoto
- Department of Biostatistics, School of Medicine, Yokohama City University, Yokohama, Japan
| | - Takako Yoshioka
- Department of Pathology, National Center for Child Health and Development, Tokyo, Japan
| | - Masayoshi Kage
- Kurume University Research Center for Innovative Cancer Therapy, Fukuoka, Japan
| | - Hisamitsu Hayashi
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo, Japan
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31
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Juarez-Navarro K, Ayala-Garcia VM, Ruiz-Baca E, Meneses-Morales I, Rios-Banuelos JL, Lopez-Rodriguez A. Assistance for Folding of Disease-Causing Plasma Membrane Proteins. Biomolecules 2020; 10:biom10050728. [PMID: 32392767 PMCID: PMC7277483 DOI: 10.3390/biom10050728] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2020] [Revised: 04/16/2020] [Accepted: 04/21/2020] [Indexed: 02/06/2023] Open
Abstract
An extensive catalog of plasma membrane (PM) protein mutations related to phenotypic diseases is associated with incorrect protein folding and/or localization. These impairments, in addition to dysfunction, frequently promote protein aggregation, which can be detrimental to cells. Here, we review PM protein processing, from protein synthesis in the endoplasmic reticulum to delivery to the PM, stressing the main repercussions of processing failures and their physiological consequences in pathologies, and we summarize the recent proposed therapeutic strategies to rescue misassembled proteins through different types of chaperones and/or small molecule drugs that safeguard protein quality control and regulate proteostasis.
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32
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Kriegermeier A, Green R. Pediatric Cholestatic Liver Disease: Review of Bile Acid Metabolism and Discussion of Current and Emerging Therapies. Front Med (Lausanne) 2020; 7:149. [PMID: 32432119 PMCID: PMC7214672 DOI: 10.3389/fmed.2020.00149] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Accepted: 04/06/2020] [Indexed: 02/06/2023] Open
Abstract
Cholestatic liver diseases are a significant cause of morbidity and mortality and the leading indication for pediatric liver transplant. These include diseases such as biliary atresia, Alagille syndrome, progressive intrahepatic cholestasis entities, ductal plate abnormalities including Caroli syndrome and congenital hepatic fibrosis, primary sclerosing cholangitis, bile acid synthesis defects, and certain metabolic disease. Medical management of these patients typically includes supportive care for complications of chronic cholestasis including malnutrition, pruritus, and portal hypertension. However, there are limited effective interventions to prevent progressive liver damage in these diseases, leaving clinicians to ultimately rely on liver transplantation in many cases. Agents such as ursodeoxycholic acid, bile acid sequestrants, and rifampicin have been mainstays of treatment for years with the understanding that they may decrease or alter the composition of the bile acid pool, though clinical response to these medications is frequently insufficient and their effects on disease progression remain limited. Recently, animal and human studies have identified potential new therapeutic targets which may disrupt the enterohepatic circulation of bile acids, alter the expression of bile acid transporters or decrease the production of bile acids. In this article, we will review bile formation, bile acid signaling, and the relevance for current and newer therapies for pediatric cholestasis. We will also highlight further areas of potential targets for medical intervention for pediatric cholestatic liver diseases.
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Affiliation(s)
- Alyssa Kriegermeier
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Feinberg School of Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Chicago, IL, United States
| | - Richard Green
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
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Effect of food on the pharmacokinetics and therapeutic efficacy of 4-phenylbutyrate in progressive familial intrahepatic cholestasis. Sci Rep 2019; 9:17075. [PMID: 31745229 PMCID: PMC6863819 DOI: 10.1038/s41598-019-53628-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Accepted: 11/04/2019] [Indexed: 12/11/2022] Open
Abstract
Progressive familial intrahepatic cholestasis (PFIC), a rare inherited disorder, progresses to liver failure in childhood. We have shown that sodium 4-phenylbutyrate (NaPB), a drug approved for urea cycle disorders (UCDs), has beneficial effects in PFIC. However, there is little evidence to determine an optimal regimen for NaPB therapy. Herein, a multicenter, open-label, single-dose study was performed to investigate the influence of meal timing on the pharmacokinetics of NaPB. NaPB (150 mg/kg) was administered orally 30 min before, just before, and just after breakfast following overnight fasting. Seven pediatric PFIC patients were enrolled and six completed the study. Compared with postprandial administration, an approved regimen for UCDs, preprandial administration significantly increased the peak plasma concentration and area under the plasma concentration-time curve of 4-phenylbutyrate by 2.5-fold (95% confidential interval (CI), 2.0-3.0;P = 0.003) and 2.4-fold (95% CI, 1.7-3.2;P = 0.005). The observational study over 3 years in two PFIC patients showed that preprandial, but not prandial or postprandial, oral treatment with 500 mg/kg/day NaPB improved liver function tests and clinical symptoms and suppressed the fibrosis progression. No adverse events were observed. Preprandial oral administration of NaPB was needed to maximize its potency in PFIC patients.
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34
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Mózner O, Bartos Z, Zámbó B, Homolya L, Hegedűs T, Sarkadi B. Cellular Processing of the ABCG2 Transporter-Potential Effects on Gout and Drug Metabolism. Cells 2019; 8:E1215. [PMID: 31597297 PMCID: PMC6830335 DOI: 10.3390/cells8101215] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 10/04/2019] [Accepted: 10/05/2019] [Indexed: 02/07/2023] Open
Abstract
The human ABCG2 is an important plasma membrane multidrug transporter, involved in uric acid secretion, modulation of absorption of drugs, and in drug resistance of cancer cells. Variants of the ABCG2 transporter, affecting cellular processing and trafficking, have been shown to cause gout and increased drug toxicity. In this paper, we overview the key cellular pathways involved in the processing and trafficking of large membrane proteins, focusing on ABC transporters. We discuss the information available for disease-causing polymorphic variants and selected mutations of ABCG2, causing increased degradation and impaired travelling of the transporter to the plasma membrane. In addition, we provide a detailed in silico analysis of an as yet unrecognized loop region of the ABCG2 protein, in which a recently discovered mutation may actually promote ABCG2 membrane expression. We suggest that post-translational modifications in this unstructured loop at the cytoplasmic surface of the protein may have special influence on ABCG2 processing and trafficking.
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Affiliation(s)
- Orsolya Mózner
- Institute of Enzymology, Research Centre for Natural Sciences, Magyar Tudosok krt. 2, 1117 Budapest, Hungary.
| | - Zsuzsa Bartos
- Institute of Enzymology, Research Centre for Natural Sciences, Magyar Tudosok krt. 2, 1117 Budapest, Hungary.
- MTA-SE Molecular Biophysics Research Group, Hungarian Academy of Sciences, Tűzoltó u. 37-47, 1094 Budapest, Hungary.
| | - Boglárka Zámbó
- Institute of Enzymology, Research Centre for Natural Sciences, Magyar Tudosok krt. 2, 1117 Budapest, Hungary.
| | - László Homolya
- Institute of Enzymology, Research Centre for Natural Sciences, Magyar Tudosok krt. 2, 1117 Budapest, Hungary.
| | - Tamás Hegedűs
- MTA-SE Molecular Biophysics Research Group, Hungarian Academy of Sciences, Tűzoltó u. 37-47, 1094 Budapest, Hungary.
- Department of Biophysics and Radiation Biology, Semmelweis University, Tűzoltó u. 37-47, 1094 Budapest, Hungary.
| | - Balázs Sarkadi
- Institute of Enzymology, Research Centre for Natural Sciences, Magyar Tudosok krt. 2, 1117 Budapest, Hungary.
- Department of Biophysics and Radiation Biology, Semmelweis University, Tűzoltó u. 37-47, 1094 Budapest, Hungary.
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Takayama K. [Pharmaceutical Research on Liver Diseases Using iPS Cell and Genome Editing Technologies]. YAKUGAKU ZASSHI 2019; 139:1219-1225. [PMID: 31582604 DOI: 10.1248/yakushi.19-00138] [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: 11/22/2022]
Abstract
The liver is a major organ responsible for maintaining the body's homeostasis and xenobiotic metabolism. Liver transplantation is essential for the alleviation of many severe liver diseases. However, there are many patients who cannot receive liver transplants because of donor shortage. Therefore development of effective therapeutic drugs that can replace the need for liver transplantation is desired. To this end, model cells that faithfully reproduce hepatic functions are essential. It is expected that human induced pluripotent stem cell (iPS)-derived hepatocyte-like cells, which faithfully reproduce hepatic functions, would be a valuable tool for drug discovery. Hepatic differentiation from human iPS cells has been performed using growth factors, but the hepatic differentiation efficiency was quite low and liver functions of human iPS cell-derived hepatocyte-like cells were lower than those of primary human hepatocytes. Therefore we tried to improve the hepatic differentiation technology using gene transfer, genome editing, three-dimensional culture, and extracellular matrix technologies. As a result, the purity of human iPS cell-derived hepatocyte-like cells was improved into 90% or more, and the liver functions of human iPS cell-derived hepatocyte-like cells were improved to a level comparable to primary human hepatocytes. In this article, we introduce the research results we have acquired over the last decade.
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Affiliation(s)
- Kazuo Takayama
- Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University.,Laboratory of Hepatocyte Regulation, National Institutes of Biomedical Innovation, Health and Nutrition.,PRESTO, Japan Science and Technology Agency
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36
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Anticholestatic mechanisms of ursodeoxycholic acid in lipopolysaccharide-induced cholestasis. Biochem Pharmacol 2019; 168:48-56. [DOI: 10.1016/j.bcp.2019.06.009] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Accepted: 06/10/2019] [Indexed: 12/14/2022]
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37
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Feldman AG, Sokol RJ. Neonatal cholestasis: emerging molecular diagnostics and potential novel therapeutics. Nat Rev Gastroenterol Hepatol 2019; 16:346-360. [PMID: 30903105 DOI: 10.1038/s41575-019-0132-z] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Neonatal cholestasis is a group of rare disorders of impaired bile flow characterized by conjugated hyperbilirubinaemia in the newborn and young infant. Neonatal cholestasis is never physiological but rather is a sign of hepatobiliary and/or metabolic disorders, some of which might be fatal if not identified and treated rapidly. A step-wise timely evaluation is essential to quickly identify those causes amenable to treatment and to offer accurate prognosis. The aetiology of neonatal cholestasis now includes an expanding group of molecularly defined entities with overlapping clinical presentations. In the past two decades, our understanding of the molecular basis of many of these cholestatic diseases has improved markedly. Simultaneous next-generation sequencing for multiple genes and whole-exome or whole-genome sequencing now enable rapid and affordable molecular diagnosis for many of these disorders that cannot be directly diagnosed from standard blood tests or liver biopsy. Unfortunately, despite these advances, the aetiology and optimal therapeutic approach of the most common of these disorders, biliary atresia, remain unclear. The goals of this Review are to discuss the aetiologies, algorithms for evaluation and current and emerging therapeutic options for neonatal cholestasis.
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Affiliation(s)
- Amy G Feldman
- Pediatric Liver Center, Digestive Health Institute, Children's Hospital Colorado, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, CO, USA
| | - Ronald J Sokol
- Pediatric Liver Center, Digestive Health Institute, Children's Hospital Colorado, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, CO, USA. .,Colorado Clinical and Translational Sciences Institute, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
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Roma MG, Barosso IR, Miszczuk GS, Crocenzi FA, Pozzi EJS. Dynamic Localization of Hepatocellular Transporters: Role in Biliary Excretion and Impairment in Cholestasis. Curr Med Chem 2019; 26:1113-1154. [DOI: 10.2174/0929867325666171205153204] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Revised: 09/06/2017] [Accepted: 09/07/2017] [Indexed: 12/25/2022]
Abstract
Bile flow generation is driven by the vectorial transfer of osmotically active compounds from sinusoidal blood into a confined space, the bile canaliculus. Hence, localization of hepatocellular transporters relevant to bile formation is crucial for bile secretion. Hepatocellular transporters are localized either in the plasma membrane or in recycling endosomes, from where they can be relocated to the plasma membrane on demand, or endocytosed when the demand decreases. The balance between endocytic internalization/ exocytic targeting to/from this recycling compartment is therefore the main determinant of the hepatic capability to generate bile, and to dispose endo- and xenobiotics. Furthermore, the exacerbated endocytic internalization is a common pathomechanisms in both experimental and human cholestasis; this results in bile secretory failure and, eventually, posttranslational transporter downregulation by increased degradation. This review summarizes the proposed structural mechanisms accounting for this pathological condition (e.g., alteration of function, localization or expression of F-actin or F-actin/transporter cross-linking proteins, and switch to membrane microdomains where they can be readily endocytosed), and the mediators implicated (e.g., triggering of “cholestatic” signaling transduction pathways). Lastly, we discussed the efficacy to counteract the cholestatic failure induced by transporter internalization of a number of therapeutic experimental approaches based upon the use of compounds that trigger exocytic targetting of canalicular transporters (e.g., cAMP, tauroursodeoxycholate). This therapeutics may complement treatments aimed to transcriptionally improve transporter expression, by affording proper localization and membrane stability to the de novo synthesized transporters.
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Affiliation(s)
- Marcelo G. Roma
- Instituto de Fisiologia Experimental (IFISE) - Facultad de Ciencias Bioquimicas y Farmaceuticas (CONICET - U.N.R.), S2002LRL, Rosario, Argentina
| | - Ismael R. Barosso
- Instituto de Fisiologia Experimental (IFISE) - Facultad de Ciencias Bioquimicas y Farmaceuticas (CONICET - U.N.R.), S2002LRL, Rosario, Argentina
| | - Gisel S. Miszczuk
- Instituto de Fisiologia Experimental (IFISE) - Facultad de Ciencias Bioquimicas y Farmaceuticas (CONICET - U.N.R.), S2002LRL, Rosario, Argentina
| | - Fernando A. Crocenzi
- Instituto de Fisiologia Experimental (IFISE) - Facultad de Ciencias Bioquimicas y Farmaceuticas (CONICET - U.N.R.), S2002LRL, Rosario, Argentina
| | - Enrique J. Sánchez Pozzi
- Instituto de Fisiologia Experimental (IFISE) - Facultad de Ciencias Bioquimicas y Farmaceuticas (CONICET - U.N.R.), S2002LRL, Rosario, Argentina
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Lipid-regulating properties of butyric acid and 4-phenylbutyric acid: Molecular mechanisms and therapeutic applications. Pharmacol Res 2019; 144:116-131. [PMID: 30954630 DOI: 10.1016/j.phrs.2019.04.002] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2018] [Revised: 02/08/2019] [Accepted: 04/01/2019] [Indexed: 12/30/2022]
Abstract
In the past two decades, significant advances have been made in the etiology of lipid disorders. Concomitantly, the discovery of liporegulatory functions of certain short-chain fatty acids has generated interest in their clinical applications. In particular, butyric acid (BA) and its derivative, 4-phenylbutyric acid (PBA), which afford health benefits against lipid disorders while being generally well tolerated by animals and humans have been assessed clinically. This review examines the evidence from cell, animal and human studies pertaining to the lipid-regulating effects of BA and PBA, their molecular mechanisms and therapeutic potential. Collectively, the evidence supports the view that intakes of BA and PBA benefit lipid homeostasis across biological systems. We reviewed the evidence that BA and PBA downregulate de novo lipogenesis, ameliorate lipotoxicity, slow down atherosclerosis progression, and stimulate fatty acid β-oxidation. Central to their mode of action, BA appears to function as a histone deacetylase (HDAC) inhibitor while PBA acts as a chemical chaperone and/or a HDAC inhibitor. Areas of further inquiry include the effects of BA and PBA on adipogenesis, lipolysis and apolipoprotein metabolism.
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Ito S. [Elucidation of Disease Mechanisms Based on Transport Function at Tissue Barriers and Challenges in Drug Development]. YAKUGAKU ZASSHI 2019; 139:497-503. [PMID: 30930376 DOI: 10.1248/yakushi.18-00153] [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: 11/22/2022]
Abstract
Tissue barriers contribute to the maintenance of homeostasis in the body, and tissue barrier dysfunction presents a risk factor for a variety of diseases. The blood-brain barrier (BBB) is a major tissue barrier acting as a static barrier and dynamic interface that plays an important role in the maintenance of central nervous system homeostasis. We show the functional characterization of the brain-to-blood efflux transport system of amyloid-β peptide (Aβ) across the BBB. We found that activated vitamin D3 may be a candidate agent for modulating the Aβ clearance across the BBB. Cerebral creatine deficiency syndromes are caused by loss-of-function mutations in the creatine transporter (CRT; SLC6A8), which transports creatine at the BBB. We found that functional impairment of CRT due to a G561R mutation resulted in incomplete N-linked glycosylation due to misfolding during protein maturation, leading to impaired creatine transport activity at the BBB. To develop a delivery system for biomedicine across the tissue barrier, we established a screening system to identify cell-penetrating peptides by a combination of in vitro cell permeability screening assays and phage display technology. Using this system, we identified cyclic hepta-peptides that are able to facilitate intestinal absorption of phages in vitro and in vivo, which are promising candidates as a carrier for macromolecular biomedicines. In conclusion, these studies focusing on the dynamic interface of tissue barriers will contribute to knowledge on disease pathogenesis as well as the development of a targeted biomedicine delivery system.
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Affiliation(s)
- Shingo Ito
- Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University
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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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Chen HL, Wu SH, Hsu SH, Liou BY, Chen HL, Chang MH. Jaundice revisited: recent advances in the diagnosis and treatment of inherited cholestatic liver diseases. J Biomed Sci 2018; 25:75. [PMID: 30367658 PMCID: PMC6203212 DOI: 10.1186/s12929-018-0475-8] [Citation(s) in RCA: 85] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Accepted: 10/03/2018] [Indexed: 12/17/2022] Open
Abstract
Background Jaundice is a common symptom of inherited or acquired liver diseases or a manifestation of diseases involving red blood cell metabolism. Recent progress has elucidated the molecular mechanisms of bile metabolism, hepatocellular transport, bile ductular development, intestinal bile salt reabsorption, and the regulation of bile acids homeostasis. Main body The major genetic diseases causing jaundice involve disturbances of bile flow. The insufficiency of bile salts in the intestines leads to fat malabsorption and fat-soluble vitamin deficiencies. Accumulation of excessive bile acids and aberrant metabolites results in hepatocellular injury and biliary cirrhosis. Progressive familial intrahepatic cholestasis (PFIC) is the prototype of genetic liver diseases manifesting jaundice in early childhood, progressive liver fibrosis/cirrhosis, and failure to thrive. The first three types of PFICs identified (PFIC1, PFIC2, and PFIC3) represent defects in FIC1 (ATP8B1), BSEP (ABCB11), or MDR3 (ABCB4). In the last 5 years, new genetic disorders, such as TJP2, FXR, and MYO5B defects, have been demonstrated to cause a similar PFIC phenotype. Inborn errors of bile acid metabolism also cause progressive cholestatic liver injuries. Prompt differential diagnosis is important because oral primary bile acid replacement may effectively reverse liver failure and restore liver functions. DCDC2 is a newly identified genetic disorder causing neonatal sclerosing cholangitis. Other cholestatic genetic disorders may have extra-hepatic manifestations, such as developmental disorders causing ductal plate malformation (Alagille syndrome, polycystic liver/kidney diseases), mitochondrial hepatopathy, and endocrine or chromosomal disorders. The diagnosis of genetic liver diseases has evolved from direct sequencing of a single gene to panel-based next generation sequencing. Whole exome sequencing and whole genome sequencing have been actively investigated in research and clinical studies. Current treatment modalities include medical treatment (ursodeoxycholic acid, cholic acid or chenodeoxycholic acid), surgery (partial biliary diversion and liver transplantation), symptomatic treatment for pruritus, and nutritional therapy. New drug development based on gene-specific treatments, such as apical sodium-dependent bile acid transporter (ASBT) inhibitor, for BSEP defects are underway. Short conclusion Understanding the complex pathways of jaundice and cholestasis not only enhance insights into liver pathophysiology but also elucidate many causes of genetic liver diseases and promote the development of novel treatments.
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Affiliation(s)
- Huey-Ling Chen
- Departments of Pediatrics, National Taiwan University College of Medicine and Children's Hospital, 17F, No. 8, Chung Shan S. Rd, Taipei, 100, Taiwan. .,Department of Medical Education and Bioethics, National Taiwan University College of Medicine, No. 1, Jen Ai Rd Section 1, Taipei, 100, Taiwan. .,Hepatitis Research Center, National Taiwan University Hospital, Changde St. No.1, Zhongzhen Dist., Taipei 100, Taiwan.
| | - Shang-Hsin Wu
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, No. 7 Chung Shan S. Rd, Taipei 100, Taiwan
| | - Shu-Hao Hsu
- Graduate Institute of Anatomy and Cell Biology, Nationatl Taiwan University College of Medicine, No. 1 Jen Ai Rd Section 1, Taipei 100, Taiwan
| | - Bang-Yu Liou
- Departments of Pediatrics, National Taiwan University College of Medicine and Children's Hospital, 17F, No. 8, Chung Shan S. Rd, Taipei, 100, Taiwan
| | - Hui-Ling Chen
- Hepatitis Research Center, National Taiwan University Hospital, Changde St. No.1, Zhongzhen Dist., Taipei 100, Taiwan
| | - Mei-Hwei Chang
- Departments of Pediatrics, National Taiwan University College of Medicine and Children's Hospital, 17F, No. 8, Chung Shan S. Rd, Taipei, 100, Taiwan.,Hepatitis Research Center, National Taiwan University Hospital, Changde St. No.1, Zhongzhen Dist., Taipei 100, Taiwan
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Kumari N, Kumar A, Thapa BR, Modi M, Pal A, Prasad R. Characterization of mutation spectrum and identification of novel mutations in ATP7B gene from a cohort of Wilson disease patients: Functional and therapeutic implications. Hum Mutat 2018; 39:1926-1941. [PMID: 30120852 DOI: 10.1002/humu.23614] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Revised: 08/09/2018] [Accepted: 08/13/2018] [Indexed: 12/13/2022]
Abstract
Wilson disease (WD), a copper metabolism disorder, occurs due to the presence of mutations in the gene encoding ATP7B, a protein that primarily facilitates hepatic copper excretion. A better understanding of spectrum and functional significance of ATP7B variants is critical to formulating targeted and personalized therapies. Henceforth, we screened and sequenced 21 exons of ATP7B gene from 50 WD patients and 60 healthy subjects. We identified 28 variants comprising, seven novels in 20% alleles, while eight variations affecting 23% alleles were first time reported in Indian cohort. The c.813C>A, p.(Cys271*) (10%) was the most frequent mutation. Bioinformatics analysis revealed five of seven novel variants viz. c.1600C>A, p.(Pro534Thr); c.1616C>A, p.(Pro539His); c.1924G>T, p.(Asp642Tyr); c.2168G>C, p.(Arg723Thr); c.2174G>C, p.(Arg725Thr) resulted in protein misfolding. Sequence conservation analysis of ATP7B regions containing novel variants documented an evolutionarily conserved nature. Functional analysis of these novel variants in five different cell lines lacking inherent ATP7B expression demonstrated sensitivity to CuCl2 -treatment, experiencing augmented cellular copper retention and decreased copper excretion as well as ceruloplasmin secretion to that of wildtype-ATP7B expressing cells. Interestingly, pharmacological chaperone 4-phenylbutyrate, a clinically approved compound, partially restored protein function of ATP7B mutants. These findings might enable novel treatment strategies in WD by clinically enhancing the protein expression of mutant ATP7B with residual copper export activity.
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Affiliation(s)
- Niti Kumari
- Department of Biochemistry, PGIMER, Chandigarh, India
| | - Aman Kumar
- Department of Biochemistry, PGIMER, Chandigarh, India
| | - Babu Ram Thapa
- Department of Paediatrics Gastroenterology, PGIMER, Chandigarh, India
| | - Manish Modi
- Department of Neurology, PGIMER, Chandigarh, India
| | - Arnab Pal
- Department of Biochemistry, PGIMER, Chandigarh, India
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Jara O, Minogue PJ, Berthoud VM, Beyer EC. Chemical chaperone treatment improves levels and distributions of connexins in Cx50D47A mouse lenses. Exp Eye Res 2018; 175:192-198. [PMID: 29913165 DOI: 10.1016/j.exer.2018.06.015] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Revised: 05/10/2018] [Accepted: 06/14/2018] [Indexed: 01/29/2023]
Abstract
Mouse Cx50D47A and human Cx50D47N are non-functional connexin mutants that cause dominantly-inherited cataracts. In tissue culture expression experiments, they both exhibit impaired cellular trafficking and gap junction plaque formation. Lenses of mice expressing Cx50D47A have cataracts, reduced size, drastically decreased levels of connexin50, and less severely reduced levels of connexin46. The PERK-dependent pathway of the ER response to misfolded proteins is activated, and they have impaired differentiation with retained cellular organelles. Since treatments that enhance protein folding improve trafficking and plaque formation by Cx50D47N and other mutant connexins in vitro, and they are successful therapeutics for some other diseases caused by misfolded proteins, we tested the efficacy of the chemical chaperone, 4-phenylbutyrate (4-PBA) in cultured cells and mice expressing Cx50D47A. 4-PBA treatment increased the formation of Cx50D47A-containing plaques at appositional membranes of transiently transfected HeLa cells. Heterozygous Cx50D47A mice were treated with 4-PBA by addition to the drinking water and parenteral injection of pregnant mice (starting 10 days after pairing of males and females) and their pups. Lenses from 1-month-old mice were examined by darkfield illumination and immunofluorescence microscopy. Protein levels were determined by immunoblotting. Cataract size and density were not detectably different between the control and the 4-PBA-treated groups. Lens size was not increased following treatment. Levels of connexin46 and connexin50 were significantly increased in lenses of 4-PBA-treated mice compared with saline-treated animals. Immunofluorescence showed an increased abundance of connexin46 immunoreactivity and puncta. The ratio of phosphorylated to total EIF2α was not altered, and levels of organellar proteins were not significantly reduced, suggesting that the ER response to misfolded proteins and differentiation were not changed. Thus, treatment with 4-PBA improved critical pathological issues in these mice (low connexin and gap junction abundance), but the magnitude of this recovery (especially for Cx50) was inadequate to impact the reduced size or the opacification of Cx50D47A lenses.
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Affiliation(s)
- Oscar Jara
- Department of Pediatrics, University of Chicago, Chicago, IL, United States
| | - Peter J Minogue
- Department of Pediatrics, University of Chicago, Chicago, IL, United States
| | - Viviana M Berthoud
- Department of Pediatrics, University of Chicago, Chicago, IL, United States
| | - Eric C Beyer
- Department of Pediatrics, University of Chicago, Chicago, IL, United States.
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Tran M, Liu Y, Huang W, Wang L. Nuclear receptors and liver disease: Summary of the 2017 basic research symposium. Hepatol Commun 2018; 2:765-777. [PMID: 30129636 PMCID: PMC6049066 DOI: 10.1002/hep4.1203] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Revised: 05/03/2018] [Accepted: 05/10/2018] [Indexed: 12/11/2022] Open
Abstract
The nuclear receptor superfamily contains important transcriptional regulators that play pleiotropic roles in cell differentiation, development, proliferation, and metabolic processes to govern liver physiology and pathology. Many nuclear receptors are ligand-activated transcription factors that regulate the expression of their target genes by modulating transcriptional activities and epigenetic changes. Additionally, the protein complex associated with nuclear receptors consists of a multitude of coregulators, corepressors, and noncoding RNAs. Therefore, acquiring new information on nuclear receptors may provide invaluable insight into novel therapies and shed light on new interventions to reduce the burden and incidence of liver diseases. (Hepatology Communications 2018;2:765-777).
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Affiliation(s)
- Melanie Tran
- Department of Physiology and Neurobiology and Institute for Systems Genomics, University of Connecticut, Storrs, CT
| | - Yanjun Liu
- Department of Diabetes Complications and Metabolism, Diabetes and Metabolism Research Institute, Beckman Research Institute City of Hope National Medical Center Duarte CA
| | - Wendong Huang
- Department of Diabetes Complications and Metabolism, Diabetes and Metabolism Research Institute, Beckman Research Institute City of Hope National Medical Center Duarte CA
| | - Li Wang
- Department of Physiology and Neurobiology and Institute for Systems Genomics, University of Connecticut, Storrs, CT.,Veterans Affairs Connecticut Healthcare System West Haven CT.,Department of Internal Medicine, Section of Digestive Diseases Yale University New Haven CT
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47
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Zhang L, Xu D, Li Q, Yang Y, Xu H, Wei Z, Wang R, Zhang W, Liu Y, Geng Y, Li S, Gao X, Yang F. N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) attenuates silicotic fibrosis by suppressing apoptosis of alveolar type II epithelial cells via mediation of endoplasmic reticulum stress. Toxicol Appl Pharmacol 2018; 350:1-10. [PMID: 29684394 DOI: 10.1016/j.taap.2018.04.025] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Revised: 04/15/2018] [Accepted: 04/18/2018] [Indexed: 01/22/2023]
Abstract
Damage to alveolar epithelial cells (AECs) caused by long-term inhalation of large amounts of silica dust plays a significant role in the pathology of silicosis. The present study was undertaken to investigate the regulatory mechanism(s) involved in type II AEC damage from silicon dioxide (SiO2) as well as the mechanism(s) related to the prevention of silicosis by the antifibrotic tetra peptide, N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP). The 2-DE results showed that SiO2 induced endoplasmic reticulum (ER) stress in A549 cells. In addition, typical apoptotic characteristics were observed using a transmission electron microscope (TEM) in A549 cells stimulated by SiO2 and in type II AECs from silicotic rats. Mechanistic study showed that both Ac-SDKP and 4-phenylbutyrate (4-PBA), an inhibiter of ER stress, attenuated GRP78, phosphor-PERK, phosphor-eIF2α, CHOP and Caspase-12 protein expression in A549 cells stimulated by SiO2 and in type II AECs from silicotic rats. Treatment with Ac-SDKP and 4-PBA in vivo effectively inhibited collagen deposition in the lungs of silicotic rats. In summary, ER stress is involved in the apoptosis of type II AECs both in vitro and in vivo. Ac-SDKP effectively suppresses SiO2-induced apoptosis in type II AECs by attenuating the Caspase-12 and PERK/eIF2α/CHOP pathway activation caused by ER stress, thus preventing silicotic fibrosis.
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Affiliation(s)
- Lijuan Zhang
- Basic Medical College, Hebei Medical University, Shijiazhuang, Hebei 050017, China
| | - Dingjie Xu
- Traditional Chinese Medicine College, North China University of Science and Technology, Tangshan, Hebei 063210, China
| | - Qian Li
- Medical Research Center, North China University of Science and Technology, Tangshan, Hebei 063210, China
| | - Yi Yang
- Department of educational affairs, North China University of Science and Technology, Tangshan, Hebei 063210, China
| | - Hong Xu
- Medical Research Center, North China University of Science and Technology, Tangshan, Hebei 063210, China
| | - Zhongqiu Wei
- Basic Medical College, North China University of Science and Technology, Tangshan, Hebei 063210, China
| | - Ruimin Wang
- Medical Research Center, North China University of Science and Technology, Tangshan, Hebei 063210, China
| | - Wenli Zhang
- Medical Research Center, North China University of Science and Technology, Tangshan, Hebei 063210, China
| | - Yan Liu
- Basic Medical College, North China University of Science and Technology, Tangshan, Hebei 063210, China
| | - Yucong Geng
- Medical Research Center, North China University of Science and Technology, Tangshan, Hebei 063210, China
| | - Shifeng Li
- Medical Research Center, North China University of Science and Technology, Tangshan, Hebei 063210, China
| | - Xuemin Gao
- Medical Research Center, North China University of Science and Technology, Tangshan, Hebei 063210, China
| | - Fang Yang
- Basic Medical College, Hebei Medical University, Shijiazhuang, Hebei 050017, China; Medical Research Center, North China University of Science and Technology, Tangshan, Hebei 063210, China.
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48
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Miszczuk GS, Barosso IR, Larocca MC, Marrone J, Marinelli RA, Boaglio AC, Sánchez Pozzi EJ, Roma MG, Crocenzi FA. Mechanisms of canalicular transporter endocytosis in the cholestatic rat liver. Biochim Biophys Acta Mol Basis Dis 2018; 1864:1072-1085. [DOI: 10.1016/j.bbadis.2018.01.015] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Revised: 01/12/2018] [Accepted: 01/16/2018] [Indexed: 01/03/2023]
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49
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Imagawa K, Hayashi H, Sabu Y, Tanikawa K, Fujishiro J, Kajikawa D, Wada H, Kudo T, Kage M, Kusuhara H, Sumazaki R. Clinical phenotype and molecular analysis of a homozygous ABCB11 mutation responsible for progressive infantile cholestasis. J Hum Genet 2018; 63:569-577. [PMID: 29507376 DOI: 10.1038/s10038-018-0431-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Revised: 02/02/2018] [Accepted: 02/07/2018] [Indexed: 01/26/2023]
Abstract
The bile salt export pump (BSEP) plays an important role in biliary secretion. Mutations in ABCB11, the gene encoding BSEP, induce progressive familial intrahepatic cholestasis type 2 (PFIC2), which presents with severe jaundice and liver dysfunction. A less severe phenotype, called benign recurrent intrahepatic cholestasis type 2, is also known. About 200 missense mutations in ABCB11 have been reported. However, the phenotype-genotype correlation has not been clarified. Furthermore, the frequencies of ABCB11 mutations differ between Asian and European populations. We report a patient with PFIC2 carrying a homozygous ABCB11 mutation c.386G>A (p.C129Y) that is most frequently reported in Japan. The pathogenicity of BSEPC129Y has not been investigated. In this study, we performed the molecular analysis of this ABCB11 mutation using cells expressing BSEPC129Y. We found that trafficking of BSEPC129Y to the plasma membrane was impaired and that the expression of BSEPC129Y on the cell surface was significantly lower than that in the control. The amount of bile acids transported via BSEPC129Y was also significantly lower than that via BSEPWT. The transport activity of BSEPC129Y may be conserved because the amount of membrane BSEPC129Y corresponded to the uptake of taurocholate into membrane vesicles. In conclusion, we demonstrated that c.386G>A (p.C129Y) in ABCB11 was a causative mutation correlating with the phenotype of patients with PFIC2, impairment of biliary excretion from hepatocytes, and the absence of canalicular BSEP expression in liver histological assessments. Mutational analysis in ABCB11 could facilitate the elucidation of the molecular mechanisms underlying the development of intrahepatic cholestasis.
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Affiliation(s)
- Kazuo Imagawa
- Department of Pediatrics, University of Tsukuba Hospital, Ibaraki, Japan. .,Department of Child Health, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan.
| | - Hisamitsu Hayashi
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
| | - Yusuke Sabu
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
| | - Ken Tanikawa
- Department of Diagnostic Pathology, Kurume University Hospital, Fukuoka, Japan
| | - Jun Fujishiro
- Department of Pediatric Surgery, Faculty of Medicine, The University of Tokyo, Tokyo, Japan
| | - Daigo Kajikawa
- Department of Pediatrics, University of Tsukuba Hospital, Ibaraki, Japan
| | - Hiroki Wada
- Department of Pediatrics, University of Tsukuba Hospital, Ibaraki, Japan
| | - Toyoichiro Kudo
- Department of Pediatrics, Mito Saiseikai General Hospital, Ibaraki, Japan
| | - Masayoshi Kage
- Department of Diagnostic Pathology, Kurume University Hospital, Fukuoka, Japan
| | - Hiroyuki Kusuhara
- Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
| | - Ryo Sumazaki
- Department of Child Health, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
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50
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Malatack JJ, Doyle D. A Drug Regimen for Progressive Familial Cholestasis Type 2. Pediatrics 2018; 141:peds.2016-3877. [PMID: 29284646 DOI: 10.1542/peds.2016-3877] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/27/2017] [Indexed: 01/01/2023] Open
Abstract
Progressive familial cholestasis type 2 is caused by a genetically determined absence or reduction in the activity of the bile salt export pump (BSEP). Reduction or absence of BSEP activity causes a failure of bile salt excretion, leading to accumulation of bile salts in hepatocytes and subsequent hepatic damage. Clinically, patients are jaundiced, suffer from severe intractable pruritus, and evidence progressive liver dysfunction. A low level of serum γ-glutamyl transpeptidase, when associated with the described signs and symptoms, is often an early identifier of this condition. Treatment options to date include liver transplantation and the use of biliary diversion. We report a multidrug regimen of 4-phenylbutyrate, oxcarbazepine, and maralixibat (an experimental drug owned by Shire Pharmaceuticals, Dublin, Republic of Ireland) that completely controlled symptoms in 2 siblings with partial loss of BSEP activity.
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Affiliation(s)
- J Jeffrey Malatack
- Nemours/Alfred I. duPont Hospital for Children, Wilmington, Delaware; and Thomas Jefferson University, Sidney Kimmel Medical College, Philadelphia, Pennsylvania
| | - Daniel Doyle
- Nemours/Alfred I. duPont Hospital for Children, Wilmington, Delaware; and Thomas Jefferson University, Sidney Kimmel Medical College, Philadelphia, Pennsylvania
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