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) |
| المصدر: | Hepatology. |
| بيانات النشر: | John Wiley & Sons, 2022. |
| سنة النشر: | 2022 |
| 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 can efficiently attenuate liver damage in these patients. 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 |
| تدمد: | 1527-3350 0270-9139 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=od______1106::45205b5aada184b7f0cdb42bc11538f0Test http://hdl.handle.net/10261/287978Test |
| رقم الانضمام: | edsair.od......1106..45205b5aada184b7f0cdb42bc11538f0 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15273350 02709139 |
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