ArticleCell transplantation2017
Estrogen-Estrogen Receptor α Signaling Facilitates Bilirubin Metabolism in Regenerating Liver Through Regulating Cytochrome P450 2A6 Expression.
Article in Cell transplantation, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 25 citations in OpenAlex.
- Gender-specific associations between serum indirect bilirubin and chronic kidney disease risk: a prospective cohort study highlighting a protective effect confined to males.BMC nephrology · 2026Article
- Sex-Specific Associations of Total Bilirubin, ALBI, and PALBI with Lung Cancer Risk: Interactions with Smoking and Alcohol.Healthcare (Basel, Switzerland) · 2025Article
- Article
- Contribution of Sex Differences to the Development of Cardiovascular Disease in Metabolic-Associated Steatotic Liver Disease (MASLD).International journal of translational medicine (Basel, Switzerland) · 2024Article
- Sex hormone receptors, calcium-binding protein and Yap1 signaling regulate sex-dependent liver cell proliferation following partial hepatectomy.Disease models & mechanisms · 2024Article
- Sex differences in the relationship between serum total bilirubin and risk of incident metabolic syndrome in community-dwelling adults: Propensity score analysis using longitudinal cohort data over 16 years.Cardiovascular diabetology · 2024Article
- Article
- Gender specific survival rates after deceased donor liver transplantation: A retrospective cohort.Annals of medicine and surgery (2012) · 2022Article
- Combined analyses of RNA-sequence and Hi-C along with GWAS loci-A novel approach to dissect keloid disorder genetic mechanism.PLoS genetics · 2022Article
- The gender-specific bidirectional relations between chronic diseases and total bilirubin/urea in the elderly population: A 3-year longitudinal study.Frontiers in public health · 2022Article
- Sex difference in the associations among liver function parameters with incident diabetes mellitus in a large Taiwanese population follow-up study.Frontiers in public health · 2022Article
- Co-expression of drug metabolizing cytochrome P450 enzymes and estrogen receptor alpha (ESR1) in human liver: racial differences and the regulatory role of ESR1.Drug metabolism and personalized therapy · 2021Article
- Liver Biochemical Abnormalities in Adolescent Patients with Turner SyndromeJournal of clinical research in pediatric endocrinology · 2019Article
- Ligand-Free Estrogen ReceptorMolecular pharmacology · 2019Article
- The association between total bilirubin and serum triglyceride in both sexes in Chinese.Lipids in health and disease · 2018Article
Corrections and comments
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Authors and funding
8 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundAfter living donor liver transplantation (LDLT), rising serum bilirubin levels commonly indicate insufficient numbers of hepatocytes are available to metabolize bilirubin into biliverdin. Recovery of bilirubin levels is an important marker of hepatocyte repopulation after LDLT. Cytochrome P450 (CYP) 2A6 in humans (or cyp2a4 in rodents) can function as "bilirubin oxidase." Functional hepatocytes contain abundant CYP2A6, which is considered a marker for hepatocyte function recovery. The aim of our study was to determine the impact of estradiol/estrogen receptor signaling on bilirubin levels during liver function recovery.
methodsWe conducted a hospital-based cohort study of bilirubin levels after LDLT surgery in both liver graft donors and recipients, performed a transcriptome comparison of wild-type versus estrogen receptor (ER)α knockout mice and a bioinformatics analysis of transcriptome changes in their regenerating liver after two-third partial hepatectomy (PHx), and assayed in vitro expression of cytochrome (CYP2A6) in human hepatic progenitor cells (HepRG) treated with 17β-estradiol (E2).
resultsThe latency of bilirubin level reduction was shorter in women than in men, suggesting that a female factor promotes bilirubin recovery after liver transplantation surgery. In the PHx mouse model, the expression of the cyp2a4 gene was significantly lower in livers from the knockout ERα mice than in livers from their wild-type littermates; but the expression of other bilirubin metabolism-related genes were similar between these groups. Moreover, E2 or bilirubin treatments significantly promoted CYP2A6 expression in hepatocyte progenitor cells (HepRG cells). Sequence analysis revealed similar levels of aryl hydrocarbon receptor (AhR; bilirubin responsive nuclear receptor) and ESR1 binding to the promoter region of CYP2A6.
conclusionsThis is the first report to demonstrate, on a molecular level, that E2/ERα signaling facilitates bilirubin metabolism in regenerating liver. Our findings contribute new knowledge to our understanding of why the latency of improved bilirubin metabolism and thereby liver function recovery is shorter in females than in males.
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