ArticlePloS one2012
Metformin reduces hepatic expression of SIRT3, the mitochondrial deacetylase controlling energy metabolism.
Article in PloS one, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 50 citations in OpenAlex.
- Hepatocyte estrogen-related receptor α modulates a gluconeogenic-epigenetic crosstalk counteracting MASLD/MASH progression.Experimental & molecular medicine · 2026Article
- Metformin increases 3-hydroxy medium chain fatty acids in patients with type 2 diabetes: a cross-sectional pharmacometabolomic study.Frontiers in endocrinology · 2024Article
- BZD9L1 Differentially Regulates Sirtuins in Liver-Derived Cells by Inducing Reactive Oxygen Species.Biomedicines · 2023Article
- Metformin extends the chronological lifespan of fission yeast by altering energy metabolism and stress resistance capacity.FEMS yeast research · 2023Article
- A bioinspired carbon monoxide delivery system prevents acute kidney injury and the progression to chronic kidney disease.Redox biology · 2022Article
- miR-378a-3p Participates in Metformin's Mechanism of Action on C2C12 Cells under Hyperglycemia.International journal of molecular sciences · 2021Article
- Ginsenoside Rg1 protects against Sca-1Experimental and therapeutic medicine · 2020Article
- The Soluble Adenylyl Cyclase Inhibitor LRE1 Prevents Hepatic Ischemia/Reperfusion Damage Through Improvement of Mitochondrial Function.International journal of molecular sciences · 2020Article
- Effect of ApoE isoforms on mitochondria in Alzheimer disease.Neurology · 2020Article
- Ginsenoside Rg1 Performs Anti-Aging Functions by Suppressing Mitochondrial Pathway-Mediated Apoptosis and Activating Sirtuin 3 (SIRT3)/Superoxide Dismutase 2 (SOD2) Pathway in Sca-1⁺ HSC/HPC Cells of an Aging Rat Model.Medical science monitor : international medical journal of experimental and clinical research · 2020Article
- Article
- Glucagon-Induced Acetylation of Energy-Sensing Factors in Control of Hepatic Metabolism.International journal of molecular sciences · 2019Review
- Mitochondrial Deacetylase SIRT3 Plays an Important Role in Donor T Cell Responses after Experimental Allogeneic Hematopoietic Transplantation.Journal of immunology (Baltimore, Md. : 1950) · 2018Article
- AMPK in skeletal muscle function and metabolism.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2018Review
- Sirtuin 3 acts as a negative regulator of autophagy dictating hepatocyte susceptibility to lipotoxicity.Hepatology (Baltimore, Md.) · 2017Article
- Interplay Between SIRT-3, Metabolism and Its Tumor Suppressor Role in Hepatocellular Carcinoma.Digestive diseases and sciences · 2017Review
- SIRT3: Oncogene and Tumor Suppressor in Cancer.Cancers · 2017Review
- SIRT1 and SIRT7 expression in adipose tissues of obese and normal-weight individuals is regulated by microRNAs but not by methylation status.International journal of obesity (2005) · 2016Article
- PGC-1α Promotes Ureagenesis in Mouse Periportal Hepatocytes through SIRT3 and SIRT5 in Response to Glucagon.Scientific reports · 2016Article
- Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Metformin inhibits ATP production in mitochondria and this may be involved in the anti-hyperglycemic effects of the drug. Sirtuin 3 (SIRT3) is a mitochondrial protein deacetylase that regulates the function of the electron transport chain and maintains basal ATP yield. We hypothesized that metformin treatment could diminish mitochondrial ATP production through downregulation of SIRT3 expression. Glucagon and cAMP induced SIRT3 mRNA in mouse primary hepatocytes. Metformin prevented SIRT3 induction by glucagon. Moreover, metformin downregulated constitutive expression of SIRT3 in primary hepatocytes and in the liver in vivo. Estrogen related receptor alpha (ERRα) mediates regulation of Sirt3 gene by peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). ERRα mRNA expression was regulated in a similar manner as SIRT3 mRNA by glucagon, cAMP and metformin. However, a higher metformin concentration was required for downregulation of ERRα than SIRT3. ERRα siRNA attenuated PGC-1α mediated induction of SIRT3, but did not affect constitutive expression. Overexpression of the constitutively active form of AMP-activated protein kinase (AMPK) induced SIRT3 mRNA, indicating that the SIRT3 downregulation by metformin is not mediated by AMPK. Metformin reduced the hepatocyte ATP level. This effect was partially counteracted by SIRT3 overexpression. Furthermore, metformin decreased mitochondrial SIRT3 protein levels and this was associated with enhanced acetylation of several mitochondrial proteins. However, metformin increased mitochondrial mass in hepatocytes. Altogether, our results indicate that metformin attenuates mitochondrial expression of SIRT3 and suggest that this mechanism is involved in regulation of energy metabolism by metformin in the liver and may contribute to the therapeutic action of metformin.
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Registered trials
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 OpenQuestion graph.