ArticleCellular and molecular gastroenterology and hepatology2020
SIRT6 Protects Against Liver Fibrosis by Deacetylation and Suppression of SMAD3 in Hepatic Stellate Cells.
Article in Cellular and molecular gastroenterology and hepatology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers.
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54 citing papers in PubMed, 91 citations in OpenAlex.
- The sirtuin family: from mechanisms to therapy.Molecular biomedicine · 2026Review
- Review
- Emerging roles of SIRT6 and its modulators in kidney diseases.Cell death discovery · 2026Review
- Role of Sirtuin 6 in the Pathogenesis of Metabolic Dysfunction-Associated Steatotic Liver Disease.Current issues in molecular biology · 2026Review
- Exercise and the hepatic sirtuin network: rethinking the research focus on SIRT1, SIRT3, and SIRT6.Frontiers in physiology · 2026Article
- Emerging Roles of Post-Translational Modifications in Metabolic Homeostasis and Type 2 Diabetes.International journal of molecular sciences · 2025Review
- Nurr1 attenuates hepatic stellate cell activation by inhibiting EMT and cell cycle progression via interaction with Smad3.Molecular biology reports · 2025Article
- Contribution of histone deacetylases (HDACs) to the regulation of histone and non-histone proteins: implications for fibrotic diseases.BMB reports · 2025Review
- The Cardiohepatic Axis in Metabolic Disease: Liver to Heart.JACC. Basic to translational science · 2025Review
- Post-translational modifications in the pathophysiological process of metabolic dysfunction‑associated steatotic liver disease.Cell & bioscience · 2025Review
- The SIRT6 Activator MDL-800 Inhibits PPARα and Fatty acid Oxidation-Related Gene Expression in Hepatocytes.Biomolecules & therapeutics · 2025Article
- Review
- Atrial Cardiomyopathy-associated Arrhythmia and the Impact of Sirtuin Signaling Pathway: A Narrative Review.Current vascular pharmacology · 2025Review
- Mechanism of IFITM1 regulating epidural scar hyperplasia after laminectomy through SMAD3/CBR4 pathway.Frontiers in immunology · 2025Article
- The role of ubiquitination and deubiquitination in the pathogenesis of non-alcoholic fatty liver disease.Frontiers in immunology · 2025Review
- Menin in Cancer.Genes · 2024Review
- Impaired SUMOylation of FoxA1 promotes nonalcoholic fatty liver disease through down-regulation of Sirt6.Cell death & disease · 2024Article
- Epigenetic and transcriptional control of adipocyte function by centenarian-associated SIRT6 N308K/A313S mutant.Clinical epigenetics · 2024Article
- Epigenetic modification in liver fibrosis: Promising therapeutic direction with significant challenges ahead.Acta pharmaceutica Sinica. B · 2024Review
- SIRT3/6: an amazing challenge and opportunity in the fight against fibrosis and aging.Cellular and molecular life sciences : CMLS · 2024Review
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10 authors at 5 institutions in 3 countries.
Funding
Abstract
BACKGROUND &
aimsNonalcoholic steatohepatitis (NASH) is a chronic liver disease that is manifested clinically by an increase in hepatic triglycerides, inflammation, and fibrosis. The pathogenesis of NASH remains incompletely understood. Sirtuin 6 (Sirt6), a nicotinamide adenine dinucleotide-dependent deacetylase, has been implicated in fatty liver disease; however, the underlying molecular mechanisms in the NASH pathogenesis are elusive. The aims of this study were to elucidate the role of hepatic Sirt6 in NASH.
methodsWild-type, liver-specific Sirt6 knockout (KO), hepatic stellate cell (HSC)-specific Sirt6 knockout (HSC-KO), and Sirt6 transgenic mice were subjected to a Western diet for 4 weeks. Hepatic phenotypes were characterized and underlying mechanisms were investigated.
resultsRemarkably, both the liver-KO and HSC-KO mice developed much worse NASH than the wild-type mice, whereas the transgenic mice were protected from the diet-induced NASH. Our cell signaling analysis showed that Sirt6 negatively regulates the transforming growth factor β-Smad family member 3 (Smad3) pathway. Biochemical analysis showed a physical interaction between Sirt6 and Smad3 in hepatic stellate cells. Moreover, our molecular data further showed that Sirt6 deacetylated Smad3 at key lysine residues K333 and K378, and attenuated its transcriptional activity induced by transforming growth factor β in hepatic stellate cells.
conclusionsOur data suggest that SIRT6 plays a critical role in the protection against NASH development and it may serve as a potential therapeutic target for NASH.
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