We have demonstrated an interplay between palmitate and monomeric TLR4–MD2 complex in mediated ROS generation selectively in macrophages but in Kupffer cells, via dynamin-dependent endocytosis of NOX2 and TLR4, and the key role of this signaling in promoting hepatic steatosis and insulin resistance in NAFLD. This evidence concerns the gene LY96 and metabolic dysfunction-associated steatotic liver disease.