ArticleBiomolecules & therapeutics2025
The SIRT6 Activator MDL-800 Inhibits PPARα and Fatty acid Oxidation-Related Gene Expression in Hepatocytes.
Article in Biomolecules & therapeutics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed.
- Peroxiredoxin II as a metabolic gatekeeper against aflatoxin BMycotoxin research · 2026Article
- SIRT6 Mediates Sterol-Dependent Feedback Regulation of Cholesterol Biosynthetic Genes in Hepatocytes.Biomolecules & therapeutics · 2026Article
- Mechanistic Links Between the Gut Microbiome and Longevity Therapeutics.Biomedicines · 2026Review
- CXCL6 exacerbates metabolic dysfunction-associated steatohepatitis by suppressing LPIN1-mediated fatty acid oxidation in hepatocytes.International journal of biological sciences · 2026Article
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Authors and funding
4 authors.
Funding
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Abstract
A histone deacetylase SIRT6 regulates the transcription of various genes involved in lipid metabolism. Fatty acid (FA) oxidation plays a pivotal role in maintaining hepatic lipid homeostasis, and its dysregulation significantly contributes to lipotoxicity and inflammation, driving the progression of steatotic liver disease. While SIRT6 is known to activate peroxisome proliferator-activated receptor-alpha (PPARα), a central regulator of FA oxidation, the development of SIRT6 activators capable of enhancing FA oxidation and mitigating steatotic liver disease has yet to be achieved. This study evaluated the effect of MDL-800, a selective SIRT6 activator, on the expression of PPARα and genes related to FA oxidation. In AML12 mouse hepatocytes, MDL-800 treatment activated SIRT6 but unexpectedly decreased the expression of PPARα and its FA oxidation-associated target genes. Furthermore, OSS128167, a selective SIRT6 inhibitor, did not reverse the suppressive effects of MDL-800 on PPARα, suggesting that MDL-800 downregulates PPARα and FA oxidation-related genes through a mechanism independent of SIRT6 activation. Mechanistic investigations revealed that MDL-800 increased the production of reactive oxygen species and activated stress kinases. The inhibition of PPARα by MDL-800 was reversed by co-treatment with the antioxidant N-acetylcysteine or the JNK inhibitor SP600125. In summary, MDL-800 suppresses PPARα and FA oxidation-related genes primarily through the induction of oxidative stress in hepatocytes, independent of its role as a SIRT6 activator.
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