Beneficial effect of ursodeoxycholic acid in patients with acyl-CoA oxidase 2 (ACOX2) deficiency-associated hypertransaminasemia
Alonso-Peña, Marta (Hospital Universitario Marqués de Valdecilla (Santander, Cantabria))
Espinosa-Escudero, Ricardo (Universidad de Salamanca)
Herraez, Elisa (Instituto de Salud Carlos III)
Briz, Oscar (Instituto de Salud Carlos III)
Cagigal, Maria Luisa (Hospital Universitario Marqués de Valdecilla (Santander, Cantabria))
González Santiago, Jesús M (Hospital Universitario de Salamanca)
Ortega-Alonso, Aida (Hospital Universitario Virgen de la Victoria (Màlaga, Andalusia))
Fernandez-Rodriguez, Conrado (Universidad Rey Juan Carlos University)
Bujanda, Luis (Hospital Universitario de Donostia (Sant Sebastià, País Basc))
Calvo Sanchez, Marta (Hospital General de Segovia)
D'Avola, Delia (Clínica Universidad de Navarra)
Londoño, Maria-Carlota
Diago, Moises (Hospital General Universitario de Valencia)
Fernandez-Checa, Jose C. (University of Southern California)
Garcia-Ruiz, Carmen (University of Southern California)
Andrade, Raúl J (Hospital Universitario Virgen de la Victoria (Màlaga, Andalusia))
Lammert, Frank (Hannover Medical School)
Prieto, Jesus (Clínica Universidad de Navarra)
Crespo García, Javier (Hospital Universitario Marqués de Valdecilla (Santander, Cantabria))
Juamperez, Javier (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Díaz-González, Álvaro (Hospital Universitario Marqués de Valdecilla (Santander, Cantabria))
Monte, Maria J. (Instituto de Salud Carlos III)
Marin, Jose J. G. (Instituto de Salud Carlos III)
Univesitat Autònoma de Barcelona

Data:	2022
Resum:	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 3α,7α,12α-trihydroxy-5β-cholestanoic acid (THCA). We aimed 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. Among 33 patients with unexplained hypertransaminasemia 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 transporters, increased reactive oxygen species production (flow cytometry), endoplasmic reticulum stress biomarkers (GRP78, CHOP, and XBP1-S/XBP1-U ratio), and BAXα expression (reverse transcription followed by quantitative polymerase chain reaction and immunoblot), whereas cell viability was decreased (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 mutagenesis) and expressed in HuH-7 cells. Functional tests to determine their ability to metabolize THCA identified six with the potential to cause ADAH. Dysfunctional ACOX2 has been found in several patients with unexplained hypertransaminasemia. This condition can be accurately identified by a noninvasive diagnostic strategy based on plasma BA profiling and ACOX2 sequencing. Moreover, UDCA treatment can efficiently attenuate liver damage in these patients.
Ajuts:	Instituto de Salud Carlos III EHD15PI05/2016 Instituto de Salud Carlos III PI19/00819 Instituto de Salud Carlos III PI20/00189
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	Hepatology, Vol. 76 (july 2022) , p. 1259-1274, ISSN 1527-3350

DOI: 10.1002/hep.32517
PMID: 35395098

16 p, 3.6 MB

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