دورية أكاديمية
Beneficial Effect of Ursodeoxycholic Acid in Patients with ACOX2 Deficiency-Associated Hypertransaminasemia
| العنوان: | Beneficial Effect of Ursodeoxycholic Acid in Patients with ACOX2 Deficiency-Associated Hypertransaminasemia |
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| المؤلفون: | Alonso-Peña, Marta, Espinosa-Escudero, Ricardo, Herraez, Elisa, Briz, Óscar, Cagigal, María Luisa, Gonzalez-Santiago, Jesús M., Ortega-Alonso, Aída, Fernandez-Rodríguez, Conrado, Bujanda, Luis, Calvo Sánchez, Marta, D´Avola, Delia, Londoño, María-Carlota, Diago, Moisés, Fernández-Checa, José C., García-Ruiz, Carmen, Andrade, Raúl J., Lammert, Frank, Prieto, Jesús, Crespo, Javier, Juamperez, Javier, Díaz-González, Álvaro, Monte, Maria J., Marín, José J. G. |
| المساهمون: | Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (España), European Commission, Fundació La Marató de TV3, Junta de Castilla y León, Centro Internacional sobre el Envejecimiento (España), National Institute on Alcohol Abuse and Alcoholism (US), National Institutes of Health (US), Generalitat de Catalunya, Agencia Estatal de Investigación (España), European Cooperation in Science and Technology, Ministerio de Educación, Cultura y Deporte (España), Ministerio de Ciencia, Innovación y Universidades (España) |
| بيانات النشر: | John Wiley & Sons |
| سنة النشر: | 2022 |
| المجموعة: | Digital.CSIC (Consejo Superior de Investigaciones Científicas / Spanish National Research Council) |
| الوصف: | Background: 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 accumulation of C27-BAs, mainly trihydroxycholestanoic acid (THCA). Aims: To investigate the prevalence of ACOX2 deficiency-associated hypertransaminasemia (ADAH), its response to ursodeoxycholic acid (UDCA), elucidate its pathophysiological mechanism and identify other inborn errors that could cause this alteration. Methods & results: Among 33 patients with unexplained hypertransaminasemia from 11 hospitals, and 13 of their relatives, 7 individuals with abnormally high C27-BA levels (>50% of total BAs) were identified by HPLC-MS/MS. The p.Arg225Trp variant was found in homozygosity (exon amplification/sequencing) in 2 patients and 3 family members. Two additional non-related patients were heterozygous carriers of different alleles: c.673C>T (p.Arg225Trp) and c.456_459del (p.Thr154fs). In ADAH patients, impaired liver expression of ACOX2, but not ACOX3, was found (immunohistochemistry). Treatment with UDCA normalized transaminases levels. Incubation of HuH-7 liver cells with THCA, which was efficiently taken up, but not through BA transporters, increased ROS production (flow cytometry), ER stress biomarkers (GRP78, CHOP and XBP1-S/XBP1-U ratio), and BAX¿ expression (RT-qPCR and immunoblot), whereas cell viability was decreased (MTT). 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 mutagenesis) and expressed in HuH-7 cells. Functional tests to determine their ability to metabolize THCA identified six with the potential to cause ADAH. Conclusion: Dysfunctional ACOX2 has been found in several patients with unexplained hypertransaminasemia. This condition can be accurately identified by a non-invasive diagnostic strategy based on plasma BA profiling and ACOX2 sequencing. Moreover, UDCA treatment ... |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | unknown |
| تدمد: | 0270-9139 |
| العلاقة: | #PLACEHOLDER_PARENT_METADATA_VALUE#; info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-111669RB-I00/ES/STARD1 Y SAB EN LA ENFERMEDAD ALCOHOLICA HUMANA: VALIDACION EN UN MODELO MURINO CON HIGADO HUMANIZADO/; info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-115055RB-I00/ES/INTERACCION DE LAS PROTEINAS MITOCONDRIALES STARD1 Y SAB EN EL DESARROLLO Y PROGRESION DE LA ENFERMEDAD DEL HIGADO GRASO NO ALCOHOLICO: INFLUENCIA DEL GENERO/; Publisher's version; http://dx.doi.org/10.1002/hep.32517Test; Sí; e-issn: 1527-3350; Hepatology 76(5): 1259-1274 (2022); http://hdl.handle.net/10261/287978Test; http://dx.doi.org/10.13039/501100004587Test; http://dx.doi.org/10.13039/501100002809Test; http://dx.doi.org/10.13039/100008666Test; http://dx.doi.org/10.13039/501100000921Test; http://dx.doi.org/10.13039/501100000780Test; http://dx.doi.org/10.13039/501100011033Test; http://dx.doi.org/10.13039/100000002Test; http://dx.doi.org/10.13039/100000027Test; http://dx.doi.org/10.13039/501100003176Test; http://dx.doi.org/10.13039/501100014180Test |
| DOI: | 10.1002/hep.32517 |
| DOI: | 10.13039/501100004587 |
| DOI: | 10.13039/501100002809 |
| DOI: | 10.13039/100008666 |
| DOI: | 10.13039/501100000921 |
| DOI: | 10.13039/501100000780 |
| DOI: | 10.13039/501100011033 |
| DOI: | 10.13039/100000002 |
| DOI: | 10.13039/100000027 |
| DOI: | 10.13039/501100003176 |
| DOI: | 10.13039/501100014180 |
| الإتاحة: | https://doi.org/10.1002/hep.32517Test https://doi.org/10.13039/501100004587Test https://doi.org/10.13039/501100002809Test https://doi.org/10.13039/100008666Test https://doi.org/10.13039/501100000921Test https://doi.org/10.13039/501100000780Test https://doi.org/10.13039/501100011033Test https://doi.org/10.13039/100000002Test https://doi.org/10.13039/100000027Test https://doi.org/10.13039/501100003176Test |
| حقوق: | open |
| رقم الانضمام: | edsbas.7D5C4BD7 |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 02709139 |
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| DOI: | 10.1002/hep.32517 |