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. The gene discussed is CYBB; the disease is metabolic dysfunction-associated steatotic liver disease.