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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...

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Autores principales: 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.
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
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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.
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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
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