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Beneficial effect of ursodeoxycholic acid in patients with acyl-CoA oxidase 2 (ACOX2) deficiency-associated hypertransaminasemia

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 accumulation of C27-BAs, mainly 3?,7?,12?-trihydroxy-5?-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. Methods and results: 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 BAX? 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. Conclusions: 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.

Otras publicaciones de la misma revista o congreso con autores/as de la Universidad de Cantabria

 Fuente: Hepatology . 2022 Nov;76(5):1259-1274

Editorial: American Association for the Study of Liver Diseases

 Año de publicación: 2022

Nº de páginas: 16

Tipo de publicación: Artículo de Revista

 DOI: 10.1002/hep.32517

ISSN: 0270-9139,1527-3350

Url de la publicación: https://www.doi.org/10.1002/hep.32517

Autores/as

ALONSO-PEÑA, MARTA

ESPINOSA-ESCUDERO, RICARDO

HERRAEZ, ELISA

BRIZ, OSCAR

CAGIGAL, MARIA LUISA

GONZALEZ-SANTIAGO, JESUS M

ORTEGA-ALONSO, AIDA

FERNANDEZ-RODRIGUEZ, CONRADO

BUJANDA, LUIS

CALVO SANCHEZ, MARTA

D AVOLA, DELIA

LONDOÑO, MARIA-CARLOTA

DIAGO, MOISES

FERNANDEZ-CHECA, JOSE C

GARCIA-RUIZ, CARMEN

ANDRADE, RAUL J

LAMMERT, FRANK

PRIETO, JESUS

JUAMPEREZ, JAVIER