Alpha-Lipoic Acid Reduces NLRP3/ASC Expression and IL-1β Release in Kupffer Cells and Improves Insulin Signaling in FL83B Hepatocytes Exposed to a Conditioned Medium

Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance and chronic inflammation. This study investigated whether alpha-lipoic acid (ALA), a redox-active compound with established anti-inflammatory properties, can inhibit the activation of the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome in lipopolysaccharide (LPS)-stimulated Kupffer cells and mitigate inflammation-induced insulin resistance in FL83B hepatocytes. Kupffer cells were pretreated with ALA prior to exposure to LPS and either adenosine triphosphate or nigericin to activate NLRP3 inflammasome. The resulting conditioned medium was collected for cytokine analysis and subsequently used to treat FL83B hepatocytes. ALA reduced LPS-induced interleukin-1β (IL-1β) secretion in a concentration-dependent manner, whereas a modest but significant decrease in tumor necrosis factor-alpha (TNF-α) was observed only at the highest dose (2000 μM; p < 0.05). Western blot analysis demonstrated that ALA suppressed the expression of NLRP3 and nuclear factor-kappa B (NF-κB) (p < 0.05) and inhibited the phosphorylation of extracellular signal-regulated kinase (ERK). Additionally, ALA preserved mitochondrial membrane potential in Kupffer cells. Kupffer cells treated with ALA (100 μM) prior to LPS stimulation significantly enhanced glucose uptake and upregulated the expression of insulin signaling related proteins, including phosphorylated phosphoinositide 3-kinase (p-PI3K), phosphorylated protein kinase B (p-Akt) and glucose transporter type 2 (GLUT2) expression, in FL83B hepatocytes cultured with a conditioned medium from LPS-primed and ATP/nigericin-stimulated Kupffer cells (p < 0.05). These findings highlight the potential of ALA as a modulator of hepatic immune-metabolic interactions and support its therapeutic relevance for managing insulin resistance in T2DM.