Cellular signallingOct 20, 2024

Sirt1 reduces liver fat in type 2 diabetes by helping cells burn fat better

Regenerative Health Weekly Brief ↗PubMed ↗DOI ↗

Updated Mar 16, 2026

Abstract

Sirtuin 1 activation may improve hepatic injury by reducing lipid droplet accumulation through the deacetylation of PGC-1α.

Decreased Sirt1 is associated with increased levels of acetylated PGC-1α in liver cells exposed to high glucose and free fatty acids.
Inactivation of PGC-1α occurs when Sirt1 levels are down-regulated, leading to potential worsening of liver health.
Activating Sirt1 improves mitochondrial function by enhancing the activity of PGC-1α, which may facilitate the oxidation of fatty acids in the liver.
The beneficial effects of Sirt1 activation on liver fat accumulation are inhibited by a PGC-1α antagonist in laboratory tests.
Sirt1-mediated deacetylation of PGC-1α could help mitigate liver damage linked to type 2 diabetes mellitus.

Simplified

Being activated by deacetylation, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) has become an important regulator of metabolic-related diseases. The activation of Sirtuin 1 (Sirt1) by resveratrol was likely to deacetylate PGC-1α. However, the role of deacetylated PGC-1α in the alleviation of activated Sirt1 on type 2 diabetes mellitus (T2DM)-related fatty liver disease (FLD) remained unexplored. The aim of this study was to investigate the potential impact of Sirt1-mediated deacetylation of PGC-1α on T2DM-associated FLD and its underlying mechanisms. Our findings revealed that, along with the decreased Sirt1, the levels of acetylated PGC-1α were up-regulated in hepatocytes co-stimulated with high glucose (HG) and free fatty acids (FFA). Down-regulated Sirt1 inactivated PGC-1α by inhibiting its deacetylation, while activating Sirt1 improved hepatic injury by reducing lipid droplet accumulation through the deacetylation of PGC-1α. However, the beneficial effects of Sirt1 activation on hepatic steatosis were inhibited by PGC-1α antagonist in vitro. Mechanistically, activating Sirt1 enhanced mitochondrial function by promoting PGC-1α activity, thereby facilitating hepatic fatty acid oxidation (FAO). In conclusion, Sirt1-mediated deacetylation of PGC-1α mitigated hepatic lipotoxicity by enhancing mitochondrial FAO, which contributed to the restoration of mitochondrial function in T2DM. The activation of Sirt1-mediated PGC-1α deacetylation might represent a promising therapeutic approach for T2DM-associated FLD.

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Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

PubMed

Sirt1 reduces liver fat in type 2 diabetes by helping cells burn fat better

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