(P03-037-23) Ginsenoside Compound K Attenuates Lipopolysaccharide-Induced Inflammation and Alterations in Energy Metabolism of Macrophages by Mediating Sirtuin 1

Objectives: Inflammation, an innate immune response mediated by macrophages, has been an important factor in the pathogenesis of various chronic diseases. Ginsenoside compound K (GCK), a major active metabolite after oral administration of ginsenosides, has been suggested to modulate inflammation, oxidative stress, and metabolic disorders. The present study investigated whether GCK can inhibit inflammation and restore alterations in energy metabolism in lipopolysaccharide (LPS)-stimulated macrophages by activating sirtuin 1 (SIRT1), an NAD⁺-dependent histone deacetylase.

Methods: RAW 264.7 macrophages were stimulated with 100 ng/ml LPS in the absence or presence of 20 μM of GCK. Expression of genes related to inflammation and oxidative stress, and cellular reactive oxygen species (ROS) accumulation were measured. SIRT1 was either inhibited by its inhibitor EX-527 or activated by resveratrol to evaluate its contribution to the effects of GCK on the NAD⁺ salvage pathway, glycolysis, and mitochondrial biogenesis. A Seahorse Extracellular Flux analyzer was used to determine the parameters involved in mitochondrial respiration.

Results: LPS suppressed SIRT1 along with increases in cellular ROS accumulation and pro-inflammatory gene expression; however, the addition of GCK elicited the opposite effects. GCK attenuated the LPS-induced upregulation of glycolytic genes and abolished the LPS-altered genes involved in the NAD⁺ salvage pathway in macrophages. LPS decreased basal, maximal, and non-mitochondrial respiration, reducing ATP production and proton leak in macrophages, which were abolished by GCK. SIRT1 inhibition increased LPS-induced inflammatory and glycolytic gene expression while decreasing genes that regulate mitochondrial biogenesis; however, its activation resulted in the opposite effects.

Conclusions: GCK exhibited anti-inflammatory and antioxidant properties with the potential to reverse the alterations of energy metabolism, including glycolysis and mitochondrial respiration, through activating SIRT1 in LPS-stimulated macrophages.

Funding Sources: This study was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (No. RS-2022-00165604).