Cargando…
Beneficial effect of ursodeoxycholic acid in patients with acyl‐CoA oxidase 2 (ACOX2) deficiency–associated hypertransaminasemia
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 3α,7α,12α‐trihydroxy‐5β‐cholestanoic acid (THCA). We aime...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9796151/ https://www.ncbi.nlm.nih.gov/pubmed/35395098 http://dx.doi.org/10.1002/hep.32517 |
_version_ | 1784860418655649792 |
---|---|
author | 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 Crespo, Javier Juamperez, Javier Diaz‐Gonzalez, Alvaro Monte, Maria J. Marin, Jose J. G. |
author_facet | 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 Crespo, Javier Juamperez, Javier Diaz‐Gonzalez, Alvaro Monte, Maria J. Marin, Jose J. G. |
author_sort | Alonso‐Peña, Marta |
collection | PubMed |
description | 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 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. 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 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. 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. |
format | Online Article Text |
id | pubmed-9796151 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-97961512022-12-30 Beneficial effect of ursodeoxycholic acid in patients with acyl‐CoA oxidase 2 (ACOX2) deficiency–associated hypertransaminasemia 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 Crespo, Javier Juamperez, Javier Diaz‐Gonzalez, Alvaro Monte, Maria J. Marin, Jose J. G. Hepatology Original Articles 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 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. 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 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. 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. John Wiley and Sons Inc. 2022-07-01 2022-11 /pmc/articles/PMC9796151/ /pubmed/35395098 http://dx.doi.org/10.1002/hep.32517 Text en © 2022 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) 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. |
spellingShingle | Original Articles 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 Crespo, Javier Juamperez, Javier Diaz‐Gonzalez, Alvaro Monte, Maria J. Marin, Jose J. G. Beneficial effect of ursodeoxycholic acid in patients with acyl‐CoA oxidase 2 (ACOX2) deficiency–associated hypertransaminasemia |
title | Beneficial effect of ursodeoxycholic acid in patients with acyl‐CoA oxidase 2 (ACOX2) deficiency–associated hypertransaminasemia |
title_full | Beneficial effect of ursodeoxycholic acid in patients with acyl‐CoA oxidase 2 (ACOX2) deficiency–associated hypertransaminasemia |
title_fullStr | Beneficial effect of ursodeoxycholic acid in patients with acyl‐CoA oxidase 2 (ACOX2) deficiency–associated hypertransaminasemia |
title_full_unstemmed | Beneficial effect of ursodeoxycholic acid in patients with acyl‐CoA oxidase 2 (ACOX2) deficiency–associated hypertransaminasemia |
title_short | Beneficial effect of ursodeoxycholic acid in patients with acyl‐CoA oxidase 2 (ACOX2) deficiency–associated hypertransaminasemia |
title_sort | beneficial effect of ursodeoxycholic acid in patients with acyl‐coa oxidase 2 (acox2) deficiency–associated hypertransaminasemia |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9796151/ https://www.ncbi.nlm.nih.gov/pubmed/35395098 http://dx.doi.org/10.1002/hep.32517 |
work_keys_str_mv | AT alonsopenamarta beneficialeffectofursodeoxycholicacidinpatientswithacylcoaoxidase2acox2deficiencyassociatedhypertransaminasemia AT espinosaescuderoricardo beneficialeffectofursodeoxycholicacidinpatientswithacylcoaoxidase2acox2deficiencyassociatedhypertransaminasemia AT herraezelisa beneficialeffectofursodeoxycholicacidinpatientswithacylcoaoxidase2acox2deficiencyassociatedhypertransaminasemia AT brizoscar beneficialeffectofursodeoxycholicacidinpatientswithacylcoaoxidase2acox2deficiencyassociatedhypertransaminasemia AT cagigalmarialuisa beneficialeffectofursodeoxycholicacidinpatientswithacylcoaoxidase2acox2deficiencyassociatedhypertransaminasemia AT gonzalezsantiagojesusm beneficialeffectofursodeoxycholicacidinpatientswithacylcoaoxidase2acox2deficiencyassociatedhypertransaminasemia AT ortegaalonsoaida beneficialeffectofursodeoxycholicacidinpatientswithacylcoaoxidase2acox2deficiencyassociatedhypertransaminasemia AT fernandezrodriguezconrado beneficialeffectofursodeoxycholicacidinpatientswithacylcoaoxidase2acox2deficiencyassociatedhypertransaminasemia AT bujandaluis beneficialeffectofursodeoxycholicacidinpatientswithacylcoaoxidase2acox2deficiencyassociatedhypertransaminasemia AT calvosanchezmarta beneficialeffectofursodeoxycholicacidinpatientswithacylcoaoxidase2acox2deficiencyassociatedhypertransaminasemia AT davoladelia beneficialeffectofursodeoxycholicacidinpatientswithacylcoaoxidase2acox2deficiencyassociatedhypertransaminasemia AT londonomariacarlota beneficialeffectofursodeoxycholicacidinpatientswithacylcoaoxidase2acox2deficiencyassociatedhypertransaminasemia AT diagomoises beneficialeffectofursodeoxycholicacidinpatientswithacylcoaoxidase2acox2deficiencyassociatedhypertransaminasemia AT fernandezchecajosec beneficialeffectofursodeoxycholicacidinpatientswithacylcoaoxidase2acox2deficiencyassociatedhypertransaminasemia AT garciaruizcarmen beneficialeffectofursodeoxycholicacidinpatientswithacylcoaoxidase2acox2deficiencyassociatedhypertransaminasemia AT andraderaulj beneficialeffectofursodeoxycholicacidinpatientswithacylcoaoxidase2acox2deficiencyassociatedhypertransaminasemia AT lammertfrank beneficialeffectofursodeoxycholicacidinpatientswithacylcoaoxidase2acox2deficiencyassociatedhypertransaminasemia AT prietojesus beneficialeffectofursodeoxycholicacidinpatientswithacylcoaoxidase2acox2deficiencyassociatedhypertransaminasemia AT crespojavier beneficialeffectofursodeoxycholicacidinpatientswithacylcoaoxidase2acox2deficiencyassociatedhypertransaminasemia AT juamperezjavier beneficialeffectofursodeoxycholicacidinpatientswithacylcoaoxidase2acox2deficiencyassociatedhypertransaminasemia AT diazgonzalezalvaro beneficialeffectofursodeoxycholicacidinpatientswithacylcoaoxidase2acox2deficiencyassociatedhypertransaminasemia AT montemariaj beneficialeffectofursodeoxycholicacidinpatientswithacylcoaoxidase2acox2deficiencyassociatedhypertransaminasemia AT marinjosejg beneficialeffectofursodeoxycholicacidinpatientswithacylcoaoxidase2acox2deficiencyassociatedhypertransaminasemia |