ArticleThe Journal of biological chemistry2014
Metformin suppresses expression of the selenoprotein P gene via an AMP-activated kinase (AMPK)/FoxO3a pathway in H4IIEC3 hepatocytes.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 81 citations in OpenAlex.
- Circulating selenoprotein P levels predict glucose-lowering and insulinotropic effects of metformin, but not alogliptin: A post-hoc analysis.Journal of diabetes investigation · 2023Trial
- Effects of eicosapentaenoic acid on serum levels of selenoprotein P and organ-specific insulin sensitivity in humans with dyslipidemia and type 2 diabetes.Journal of diabetes investigation · 2022Trial
- Selenoprotein P deficiency in MASLD: association with insulin resistance and liver fibrosis: a prospective case-control study.BMC gastroenterology · 2026Article
- Emerging Insights into the Liver-Pancreas Axis: A Central Hub in the Pathogenesis of Diabetes and Metabolic Diseases.Biomolecules · 2026Review
- Metformin Impairs Breast Cancer Growth through the Inhibition of PRMT6.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- TheJournal of the Endocrine Society · 2025Article
- Article
- Hepatokines: unveiling the molecular and cellular mechanisms connecting hepatic tissue to insulin resistance and inflammation.Acta diabetologica · 2024Review
- Ethanol enhances selenoprotein P expression via ERK-FoxO3a axis in HepG2 cells.Journal of clinical biochemistry and nutrition · 2024Article
- Relationship between the changes in hepatokine levels and metabolic effects after laparoscopic sleeve gastrectomy in severely obese patients.Surgery today · 2024Article
- New-onset autoantibodies to selenoprotein P following severe burn injury.Frontiers in immunology · 2024Article
- The Role of Selenium Nanoparticles in Addressing Diabetic Complications: A Comprehensive Study.Current topics in medicinal chemistry · 2024Review
- "Alphabet" Selenoproteins: Implications in Pathology.International journal of molecular sciences · 2023Review
- Sulforaphane decreases serum selenoprotein P levels through enhancement of lysosomal degradation independent of Nrf2.Communications biology · 2023Article
- Lower Plasma Selenoprotein P Levels in Regularly Exercising Young Adults.Journal of the ASEAN Federation of Endocrine Societies · 2023Article
- Selenium and Selenoproteins at the Intersection of Type 2 Diabetes and Thyroid Pathophysiology.Antioxidants (Basel, Switzerland) · 2022Review
- Pharmacological Induction of Fetal Hemoglobin in β-Thalassemia and Sickle Cell Disease: An Updated Perspective.Pharmaceuticals (Basel, Switzerland) · 2022Review
- Emerging roles of selenium on metabolism and type 2 diabetes.Frontiers in nutrition · 2022Review
- Article
- Identification of a novel endogenous long non-coding RNA that inhibits selenoprotein P translation.Nucleic acids research · 2021Article
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Authors and funding
16 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Selenoprotein P (SeP; encoded by SEPP1 in humans) is a liver-derived secretory protein that induces insulin resistance in type 2 diabetes. Suppression of SeP might provide a novel therapeutic approach to treating type 2 diabetes, but few drugs that inhibit SEPP1 expression in hepatocytes have been identified to date. The present findings demonstrate that metformin suppresses SEPP1 expression by activating AMP-activated kinase (AMPK) and subsequently inactivating FoxO3a in H4IIEC3 hepatocytes. Treatment with metformin reduced SEPP1 promoter activity in a concentration- and time-dependent manner; this effect was cancelled by co-administration of an AMPK inhibitor. Metformin also suppressed Sepp1 gene expression in the liver of mice. Computational analysis of transcription factor binding sites conserved among the species resulted in identification of the FoxO-binding site in the metformin-response element of the SEPP1 promoter. A luciferase reporter assay showed that metformin suppresses Forkhead-response element activity, and a ChIP assay revealed that metformin decreases binding of FoxO3a, a direct target of AMPK, to the SEPP1 promoter. Transfection with siRNAs for Foxo3a, but not for Foxo1, cancelled metformin-induced luciferase activity suppression of the metformin-response element of the SEPP1 promoter. The overexpression of FoxO3a stimulated SEPP1 promoter activity and rescued the suppressive effect of metformin. Metformin did not affect FoxO3a expression, but it increased its phosphorylation and decreased its nuclear localization. These data provide a novel mechanism of action for metformin involving improvement of systemic insulin sensitivity through the regulation of SeP production and suggest an additional approach to the development of anti-diabetic drugs.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.