Sodium Butyrate Ameliorates Hepatic Steatosis and Insulin Resistance in MASLD Models With Concurrent Alterations in AMPK and PI3K/AKT Signaling

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by dysregulated glucose and lipid metabolism and is closely linked to insulin resistance (IR). Sodium butyrate (NaB) is a short-chain fatty acid with reported metabolic benefits, but its effects on MASLD-related IR remain unclear. This study investigated the therapeutic efficacy of NaB in both palmitate (PA)-induced insulin-resistant hepatocytes and high-fat diet (HFD)-induced MASLD in mice and to elucidate the underlying mechanisms responsible for its effects. Methods: We evaluated the effects of NaB in PA-treated HepG2 cells and in C57BL/6 mice fed an HFD for 16 weeks followed by 8 weeks of oral NaB administration. Lipid accumulation, glucose metabolism, glycogen storage, transcriptomic changes, and adenosine monophosphate-activated protein kinase (AMPK) and phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling were assessed using biochemical assays, staining, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), western blotting, RNA sequencing, and detection of inflammatory activity. Results: In PA-treated HepG2 cells, NaB reduced lipid accumulation, improved glucose uptake and glycogen storage, and reduced the secretion of the pro-inflammatory mediators tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), and monocyte chemoattractant protein-1 (MCP-1) in a dose-dependent manner. These effects were accompanied by the restoration of G protein-coupled receptor 43 (GPR43)/calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2)/AMPKα/sirtuin 1 (SIRT1) signaling and the activation of PI3K/AKT signaling, with decreased lipogenesis, enhanced fatty acid oxidation, reduced gluconeogenic gene expression, and alleviation of the cellular inflammatory response. In HFD-fed mice, NaB reduced body weight gain, improved serum and hepatic lipid profiles, attenuated hepatic steatosis, improved glucose tolerance and insulin sensitivity, and increased hepatic glycogen storage, while markedly lowering circulating and intrahepatic pro-inflammatory cytokine levels and downregulating hepatic expression of the macrophage marker F4/80 to mitigate inflammatory infiltration of the liver. Conclusion: These results demonstrate that NaB administration alleviated hepatic steatosis and IR in MASLD models, with these effects coinciding with the coordinated regulation of AMPK and PI3K/AKT signaling. While NaB may serve as a metabolic modulator, further mechanistic validation of dual-pathway crosstalk, characterization of inflammatory responses, and translational research are still needed.