ArticleHepatology (Baltimore, Md.)2022
Beneficial effect of ursodeoxycholic acid in patients with acyl-CoA oxidase 2 (ACOX2) deficiency-associated hypertransaminasemia.
Article in Hepatology (Baltimore, Md.), 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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16 citing papers in PubMed, 18 citations in OpenAlex.
- Beneficial Effects of Ursodeoxycholic Acid on Metabolic Parameters and Oxidative Stress in Patients with Type 2 Diabetes Mellitus: A Randomized Double-Blind, Placebo-Controlled Clinical Study.Journal of diabetes research · 2024Trial
- Peroxisomes in Liver Diseases: From Metabolite Quality Control to Inter-Organelle and Inter-Organ Signaling.Biomolecules · 2026Review
- Gut-to-bile transfer of microbially amidated minor bile acids in patients with hepatopancreatobiliary disorders.Hepatology (Baltimore, Md.) · 2026Article
- Integrated analysis of gut microbiota structure and metabolic function in patients with cirrhosis and refractory ascites.Biomedical reports · 2026Article
- Article
- Screening for Mutations Causing ACOX2 Deficiency-associated Hypertransaminasemia in Patients with Cryptogenic Liver Injury.Journal of clinical and translational hepatology · 2025Article
- Treatment of Inborn Errors by Product Replacement: The Example of Inborn Errors of Bile Acid Synthesis.Journal of inherited metabolic disease · 2025Review
- Unexplained Chronically Elevated Aminotransferases: Liver Biopsy Gives Major Information with Therapeutic Implication in One Patient Out of Seven.Digestive diseases and sciences · 2025Article
- Disorders of fatty acid homeostasis.Journal of inherited metabolic disease · 2025Review
- Synthesis, Characterization, and Potential Usefulness in Liver Function Assessment of Novel Bile Acid Derivatives with Near-Infrared Fluorescence (NIRBAD).Bioconjugate chemistry · 2024Article
- Whole-exome sequencing for genetic diagnosis of idiopathic liver injury in children.Journal of cellular and molecular medicine · 2024Article
- Article
- Fibrosis-Related Gene Profiling in Liver Biopsies of PiZZ α1-Antitrypsin Children with Different Clinical Courses.International journal of molecular sciences · 2023Article
- The zhuyu pill relieves rat cholestasis by regulating the mRNA expression of lipid and bile metabolism associated genes.Frontiers in pharmacology · 2023Article
- Article
- Beneficial effect of ursodeoxycholic acid in patients with acyl-CoA oxidase 2 (ACOX2) deficiency-associated hypertransaminasemia.Hepatology (Baltimore, Md.) · 2022Article
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Authors and funding
23 authors at 11 institutions in 3 countries.
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No grant is acknowledged in the PubMed record.
Abstract
BACKGROUND AND
aimsA 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
resultsAmong 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.
conclusionsDysfunctional 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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