Activation of a Novel c-Myc-miR27-Prohibitin 1 Circuitry in Cholestatic Liver Injury Inhibits Glutathione Synthesis in Mice
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Aims: We showed that chronic cholestatic liver injury induced the expression of c-Myc but suppressed that of glutamate-cysteine ligase (GCL, composed of catalytic and modifier subunits GCLC and GCLM, respectively). This was associated with reduced nuclear antioxidant response element (ARE) binding by nuclear factor-erythroid 2 related factor 2 (Nrf2). Here, we examined whether c-Myc is involved in this process. Results: Similar to bile duct ligation (BDL), lithocholic acid (LCA) treatment in vivo induced c-Myc but suppressed GCL subunits expression at day 14. Nrf2 expression and Nrf2 ARE binding fell markedly. However, Nrf2 heterodimerization with MafG was enhanced by LCA, which prompted us to examine whether LCA treatment in vivo altered proteins that bind to ARE using biotinylated ARE in pull-down assay followed by proteomics. LCA treatment enhanced c-Myc but lowered prohibitin 1 (PHB1) binding to ARE. This was a result of c-Myc-mediated induction of microRNA 27a/b (miR27a/b), which target both PHB1 and Nrf2 to reduce their expression. Knockdown of c-Myc or miR27a/b attenuated LCA-mediated suppression of Nrf2, PHB1, and GCL subunit expression, whereas overexpression of PHB1 protected against the fall in Nrf2 and GCL subunits. Both c-Myc and PHB1 directly interact with Nrf2 but c-Myc lowers Nrf2 binding to ARE while PHB1 enhances it. Innovation: This is the first work that shows how activation of this circuit in cholestatic liver injury inhibits GCL expression. Conclusions: LCA feeding and BDL activate c-Myc-miR27a/b-PHB1 circuit, with the consequence of inhibiting Nrf2 expression and ARE binding, resulting in decreased reduced glutathione synthesis and antioxidant capacity. Antioxid. Redox Signal. 22, 259–274.
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CHR reduces c-Myc mRNA levels in both WT and CarKO mice post-PHx.
“In line with previous findings that elevated BAs can induce c-Myc expression,37,38 CHR reduced c-Myc mRNA levels in both WT and CarKO mice post-PHx (Figure 9A).”
From Constitutive Androstane Receptor Regulates Bile Acid Homeostasis and Metabolism During Liver Regeneration (2026) · cites this paper as [38]
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Роль микроРНК, регулирующих гены окислительного стресса, при синдроме поликистозных яичниковPreprint
Lomteva, S. V., Сагомонов, А., & Kharchenko, E. Y. (2025) · doi:10.24108/preprints-3114011
de Gregório, E., Mendes, G. C., Somensi, L. B., Freire, C. G., Lopes, L. F., Lima, K. R., Carrazoni, G. S., Neves, B.-H. S., Picua, S. S., da Silva, L. M., et al. (2022) · Figshare · doi:10.6084/m9.figshare.19581932
de Gregório, E., Mendes, G. C., Somensi, L. B., Freire, C. G., Lopes, L. F., Lima, K. R., Carrazoni, G. S., Neves, B.-H. S., Picua, S. S., da Silva, L. M., et al. (2022) · Figshare · doi:10.6084/m9.figshare.19581935
- Authors
- Yang, H., Li, T. W. H., Zhou, Y., Peng, H., Liu, T., Zandi, E., Martínez-Chantar, M. L., Mato, J. M., & Lu, S. C.
- Affiliations
- University of Southern California (US)
- Central South University (CN)
- CIC bioGUNE
- CIC bioGUNE (ES)
- Corresponding author
- Lu, Shelly C.
- Venue
- Antioxidants & Redox Signaling
- Publisher
- SAGE Publications
- Published
- 2015-01
- Volume
- 22
- Issue
- 3
- Pages
- 259-274
- ISSN
- 1523-0864 (ISSN-L)
- 1557-7716
- PMC
- PMC4283066
- OpenAlex
- W1976922686
- Cited by
- 61
- References
- 34
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 3 · 2023: 3 · 2022: 11 · 2021: 4 · 2020: 11 · 2019: 7 · 2018: 4 · 2017: 2 · 2016: 3 · 2015: 8
- FWCI
- 1.78
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Antioxidants and Redox Signaling (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Eusko Jaurlaritza
- National Institutes of Health
- Instituto de Salud Carlos III (PI11/, PI11/01588)
- National Cancer Institute (R01CA172086)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK092407, P30-DK-48522, P30DK048522)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- c-Myc, prohibitin 1, Nrf2, glutathione synthesis, gamma-glutamylcysteine synthetase, cholestatic liver injury, lithocholic acid, bile duct ligation, antioxidant response element, MAFG, antioxidant capacity, microRNA regulation
- MeSH terms
- Prohibitins, Animals, Base Sequence, Binding Sites, Cholestasis, Intrahepatic, Glutamate-Cysteine Ligase, Glutathione, Humans, Male, Mice, Inbred C57BL, Protein Binding, Repressor Proteins, Gene Expression, Proto-Oncogene Proteins c-myc, RNA Interference, MicroRNAs, Cell Line, Tumor, NF-E2-Related Factor 2, Antioxidant Response Elements
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