Beneficial effect of ursodeoxycholic acid in patients with acyl-CoA oxidase 2 (ACOX2) deficiency-associated hypertransaminasemia
dc.contributor.author | Alonso Peña, Marta | |
dc.contributor.author | Espinosa Escudero, Ricardo | |
dc.contributor.author | Herráez Aguilar, Elisa | |
dc.contributor.author | Briz Sánchez, Oscar | |
dc.contributor.author | Cagigal, María Luisa | |
dc.contributor.author | González Santiago, Jesús M. | |
dc.contributor.author | Ortega Alonso, Aida | |
dc.contributor.author | Fernández Rodríguez, Conrado | |
dc.contributor.author | Bujanda Fernández de Pierola, Luis | |
dc.contributor.author | Calvo Sánchez, Marta | |
dc.contributor.author | D'Avola, Delia | |
dc.contributor.author | Londono, Maria Carlota | |
dc.contributor.author | Diago, Moisés | |
dc.contributor.author | Fernández Checa, José Carlos | |
dc.contributor.author | García Ruiz, Carmen | |
dc.contributor.author | Andrade, Raúl | |
dc.contributor.author | Lammert, Frank | |
dc.contributor.author | Prieto, Jesús | |
dc.contributor.author | Crespo, Javier | |
dc.contributor.author | Juanpérez, Javier | |
dc.contributor.author | Díaz González, Álvaro | |
dc.contributor.author | Monte, María J. | |
dc.contributor.author | García Marín, Jose Juan | |
dc.date.accessioned | 2023-02-09T17:17:50Z | |
dc.date.available | 2023-02-09T17:17:50Z | |
dc.date.issued | 2022-11 | |
dc.identifier.citation | Hepatology 76(5) : 1259-1274 (2022) | es_ES |
dc.identifier.issn | 0270-9139 | |
dc.identifier.issn | 1527-3350 | |
dc.identifier.uri | http://hdl.handle.net/10810/59742 | |
dc.description.abstract | Background and Aims: A variant (p.Arg225Trp) of peroxisomal acyl-CoA oxidase 2 (ACOX2), involved in bile acid (BA) side-chain shortening, has been associated with unexplained persistent hypertransaminasemia and accumu-lation of C27-BAs, mainly 3α,7α,12α- trihydroxy- 5β- cholestanoic acid (THCA). We aimed to investigate the prevalence of ACOX2 deficiency-associated hy-pertransaminasemia (ADAH), its response to ursodeoxycholic acid (UDCA), elucidate its pathophysiological mechanism and identify other inborn errors that could cause this alteration.Methods and Results: Among 33 patients with unexplained hypertransami-nasemia from 11 hospitals and 13 of their relatives, seven individuals with abnormally high C27-BA levels (>50% of total BAs) were identified by high- performance liquid chromatography-mass spectrometry. The p.Arg225Trp variant was found in homozygosity (exon amplification/sequencing) in two patients and three family members. Two additional nonrelated patients were heterozygous carriers of different alleles: c.673C>T (p.Arg225Trp) and c.456_459del (p.Thr154fs). In patients with ADAH, impaired liver expression of ACOX2, but not ACOX3, was found (immunohistochemistry). Treatment with UDCA normalized aminotransferase levels. Incubation of HuH-7 hepatoma cells with THCA, which was efficiently taken up, but not through BA transport-ers, increased reactive oxygen species production (flow cytometry), endo-plasmic reticulum stress biomarkers (GRP78, CHOP, and XBP1- S/ XBP1- Uratio), and BAXα expression (reverse transcription followed by quantitative polymerase chain reaction and immunoblot), whereas cell viability was de-creased (tetrazolium salt-based cell viability test). THCA-induced cell toxicity was higher than that of major C24-BAs and was not prevented by UDCA. Fourteen predicted ACOX2 variants were generated (site-directed mutagen-esis) and expressed in HuH-7 cells. Functional tests to determine their ability to metabolize THCA identified six with the potential to cause ADAH.Conclusions: Dysfunctional ACOX2 has been found in several patients with unexplained hypertransaminasemia. This condition can be accurately identi-fied by a noninvasive diagnostic strategy based on plasma BA profiling and ACOX2 sequencing. Moreover, UDCA treatment can efficiently attenuate liver damage in these patients. | es_ES |
dc.description.sponsorship | This study was supported by the following grants: CIBERehd (EHD15PI05/2016); Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Spain (PI19/00819 and PI20/00189), co-funded by European Regional Development Fund/European Social Fund, “Investing in your future”; “Junta de Castilla y León” (SA074P20); Fundació Marato TV3 (201916–31); AECC Scientific Foundation (2017/2020), Spain; and “Centro Internacional sobre el Envejecimiento” (OLD- HEPAMARKER, 0348_CIE_6_E), Spain. We also acknowledge support from grants PID2019- 111669RBI- 100, PID2020- 115055RB- I00 from Plan Nacional de I+D funded by the “Agencia Estatal de Investigación” (AEI) and the center grant P50AA011999 Southern California Research Center for ALPD and Cirrhosis funded by NIAAA/NIH, as well as support from AGAUR of the “Generalitat de Catalunya” SGR- 2017-1112, European Cooperation in Science & Technology (COST) ACTION CA17112 Prospective European Drug-Induced Liver Injury Network. Marta Alonso-Peña was the recipient of a predoctoral fellowship from “Ministerio de Educación, Cultura y Deporte” (BOE-A- 2015-9456; FPU-14/00214) and a Mobility Grant for Short Stays from “Ministerio de Ciencia, Innovación y Universidades” (EST17/00186). Ricardo Espinosa-Escudero is the recipient of a predoctoral fellowship from “Junta de Castilla y León” and “Fondo Social Europeo” (EDU/574/2018). The funding sources were not involved in the research design or preparation of the article | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | Wiley | es_ES |
dc.relation | info:eu-repo/grantAgreement/MICINN/ PID2019-111669RBI-100 | es_ES |
dc.relation | info:eu-repo/grantAgreement/MICINN/PID2020-115055RB-I00 | es_ES |
dc.rights | info:eu-repo/semantics/openAccess | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/3.0/es/ | * |
dc.title | Beneficial effect of ursodeoxycholic acid in patients with acyl-CoA oxidase 2 (ACOX2) deficiency-associated hypertransaminasemia | es_ES |
dc.type | info:eu-repo/semantics/article | es_ES |
dc.rights.holder | © 2022 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. | es_ES |
dc.rights.holder | Atribución-NoComercial-SinDerivadas 3.0 España | * |
dc.relation.publisherversion | https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.32517 | es_ES |
dc.identifier.doi | 10.1002/hep.32517 | |
dc.departamentoes | Medicina | es_ES |
dc.departamentoeu | Medikuntza | es_ES |
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Except where otherwise noted, this item's license is described as © 2022 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.