4-phenylbutyrate enhances the cell surface expression and the transport capacity of wild-type and mutated bile salt export pumps

Hayashi, Hisamitsu; Sugiyama, Yuichi

doi:10.1002/hep.21630

Cited by 161 publications

(153 citation statements)

References 39 publications

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“…Thus, maintaining low calcium levels in the ER using the calcium pump inhibitor thapsigargin or other chemicals allows to correct abnormal protein trafficking of ⌬F508 CFTR (23,35) of certain mutants of the V2 vasopressin receptor (36) or of LQT2 channels (25). Another agent, 4-PB, is also able to functionally rescue a number of trafficdefective mutant membrane proteins, including ⌬F508 CFTR (22,33), mutants of the bone morphogenic protein receptor (27), of the epithelial sodium channel (37), the low-density lipoprotein receptor (26), ATP8B1 (38), and the ABC transporter ABCB11 responsible for biliary secretion of bile salts (24). The mechanism of 4-PB rescue is not yet well understood, but one of its effects is to reduce the expression of Hsc70 and increase Hsp70 (22,39).…”

Section: Discussionmentioning

confidence: 99%

Effects of Cellular, Chemical, and Pharmacological Chaperones on the Rescue of a Trafficking-defective Mutant of the ATP-binding Cassette Transporter Proteins ABCB1/ABCB4

Gautherot

Durand‐Schneider

Delautier

et al. 2012

Journal of Biological Chemistry

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Background: Mutations of ABCB4, a transporter highly homologous to ABCB1, cause severe liver disease. Results: The I541F mutation induces misfolding and intracellular retention that is rescued by the ABCB1-competitive substrate cyclosporin A but not by modulating the chaperones calnexin or Hsp/Hsc70. Conclusion: Pharmacological chaperones are potential therapeutic tools for ABCB4 misfolded mutants. Significance: This opens perspectives to treat ABCB4-linked genetic diseases.

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Section: Discussionmentioning

confidence: 99%

Effects of Cellular, Chemical, and Pharmacological Chaperones on the Rescue of a Trafficking-defective Mutant of the ATP-binding Cassette Transporter Proteins ABCB1/ABCB4

Gautherot

Durand‐Schneider

Delautier

et al. 2012

Journal of Biological Chemistry

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“…A recent study introduced E297G and D482G into human BSEP and assessed their trafficking in MDCK cells. 66 The addition of sodium 4-phenylbutyrate prolonged the half-life of both mutant BSEP forms and resulted in increased functional expression of the proteins. This concurs with the data presented here, which show reduced levels of mature BSEP when E297G and D482G were expressed in vitro (Fig.…”

Section: Discussionmentioning

confidence: 99%

Missense mutations and single nucleotide polymorphisms in ABCB11 impair bile salt export pump processing and function or disrupt pre-messenger RNA splicing #

et al. 2009

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The gene encoding the human bile salt export pump (BSEP), ABCB11, is mutated in several forms of intrahepatic cholestasis. Here we classified the majority (63) of known ABCB11 missense mutations and 21 single-nucleotide polymorphisms (SNPs) to determine whether they caused abnormal ABCB11 pre-messenger RNA splicing, abnormal processing of BSEP protein, or alterations in BSEP protein function. Using an in vitro minigene system to analyze splicing events, we found reduced wild-type splicing for 20 mutations/SNPs, with normal mRNA levels reduced to 5% or less in eight cases. The common ABCB11 missense mutation encoding D482G enhanced aberrant splicing, whereas the common SNP A1028A promoted exon skipping. Addition of exogenous splicing factors modulated several splicing defects. Of the mutants expressed in vitro in CHO-K1 cells, most appeared to be retained in the endoplasmic reticulum and degraded. A minority had BSEP levels similar to wild-type. The SNP variant A444 had reduced levels of protein compared with V444. Treatment with glycerol and incubation at reduced temperature overcame processing defects for several mutants, including E297G. Taurocholate transport by two assessed mutants, N490D and A570T, was reduced compared with wild-type. Conclusion: This work is a comprehensive analysis of 80% of ABCB11 missense mutations and singlenucleotide polymorphisms at pre-mRNA splicing and protein processing/functional levels. We show that aberrant pre-mRNA splicing occurs in a considerable number of cases, leading to reduced levels of normal mRNA. Thus, primary defects at either the protein or the mRNA level (or both) contribute significantly to BSEP deficiency. These results will help to develop mutation-specific therapies for children and adults suffering from intrahepatic cholestasis due to BSEP deficiency. (HEPATOLOGY 2009;49:553-567.)

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“…Abnormal (typically reduced) marking may also result from decreased protein production or defective sorting or instability of an otherwise functional protein. Such patients in particular may be amenable to therapeutic interventions such as PEBD or the use of pharmacological agents which enhance BSEP cell-surface expression, e.g., 4-phenylbutyrate 55 .…”

Section: [Mdr1] and Multidrug Resistance 3 [Mdr3] Proteins)mentioning

confidence: 99%

Severe Bile Salt Export Pump Deficiency: 82 Different ABCB11 Mutations in 109 Families

et al. 2008

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BACKGROUND & AIMS:Patients with severe bile salt export pump (BSEP) deficiency present as infants with progressive cholestatic liver disease. We characterized mutations of ABCB11 (encoding BSEP) in such patients and correlated genotypes with residual protein detection and risk of malignancy. METHODS: Patients with intrahepatic cholestasis suggestive of BSEP deficiency were investigated by single-strand conformation polymorphism analysis and sequencing of ABCB11. Genotypes sorted by likely phenotypic severity were correlated with data on BSEP immunohistochemistry and clinical outcome. RESULTS: Eighty-two different mutations (52 novel) were identified in 109 families (9 nonsense mutations, 10 small insertions and deletions, 15 splice-site changes, 3 whole-gene deletions, 45 missense changes). In 7 families, only a single heterozygous mutation was identified despite complete sequence analysis. Thirty-two percent of mutations occurred in >1 family, with E297G and/or D482G present in 58% of European families (52/89). On immunohistochemical analysis (88 patients), 93% had abnormal or absent BSEP staining. Expression varied most for E297G and D482G, with some BSEP detected in 45% of patients (19/42) with these mutations. Hepatocellular carcinoma or cholangiocarcinoma developed in 15% of patients (19/128). Two protein-truncating mutations conferred particular risk; 38% (8/21) of such patients developed malignancy versus 10% (11/107) with potentially less severe genotypes (relative risk, 3.7 [confidence limits, 1.7-8.1; P = .003]). CONCLUSIONS: With this study, >100 ABCB11 mutations are now identified. Immunohistochemically detectable BSEP is typically absent, or much reduced, in severe disease. BSEP deficiency confers risk of hepatobiliary malignancy. Close surveillance of BSEP-deficient patients retaining their native liver, particularly those carrying 2 null mutations, is essential. Abbreviations:ABC, ATP-binding cassette; AFP, α-fetoprotein; BSEP, bile salt export pump; CpG, cytosine-guanine; CC, cholangiocarcinoma; FIC1, familial intrahepatic cholestasis 1; γ-GT, γ-glutamyl transferase; HCC, hepatocellular carcinoma; IC, intracellular loop; MDR1, multidrug resistance protein 1; MDR3, multidrug resistance protein 3; MRP2, multidrug resistance-associated protein 2; NBF, nucleotide-binding fold; OLT, orthotopic liver transplantation; PEBD, partial external biliary diversion; PFIC, progressive familial intrahepatic cholestasis; PCR, polymerase chain reaction; RE, restriction endonuclease; SSCP, single-strand conformation polymorphism; TM, transmembrane domain; UDCA, ursodeoxycholic acid Acknowledgements We thank the families and the Children's Liver Disease Foundation for support and encouragement, and those who referred families for analysis, including Drs U Baumann, W Berquist, M de Vree, K Emerick, G Ferry, M Finegold, W Hardikar, S Horslen, R Houwen, R Jaffe, L Klomp, F Lacaille, K Mann, P McKiernan, H Sharp, R Sokol, E Sturm, L Szönyi, J Taminou, and J Watkins. We also thank Dr R Garcia-Kennedy for access...

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4-phenylbutyrate enhances the cell surface expression and the transport capacity of wild-type and mutated bile salt export pumps

Cited by 161 publications

References 39 publications

Effects of Cellular, Chemical, and Pharmacological Chaperones on the Rescue of a Trafficking-defective Mutant of the ATP-binding Cassette Transporter Proteins ABCB1/ABCB4

Effects of Cellular, Chemical, and Pharmacological Chaperones on the Rescue of a Trafficking-defective Mutant of the ATP-binding Cassette Transporter Proteins ABCB1/ABCB4

Missense mutations and single nucleotide polymorphisms in ABCB11 impair bile salt export pump processing and function or disrupt pre-messenger RNA splicing #

Severe Bile Salt Export Pump Deficiency: 82 Different ABCB11 Mutations in 109 Families

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