Kupffer cells in non-alcoholic fatty liver disease: The emerging view

Scheme for dysfunctional activation of Kupffer cells in NAFLD. Pattern recognition receptors of Kupffer cells such as TLR4 may be increasingly exposed to exogenous and endogenous danger signals (e.g., LPS, excess fatty acids, modified lipoproteins) via the portal circulation, enhanced by lack of hepatocellular clearance. Pattern recognition pathways may intensify due to altered sorting and signalling, impaired inhibitory circuits, or amplification of redox-sensitive signalling loops. Adipokine imbalance may contribute to these events including low adiponectin levels that fail to suppress intracellular ROS generation. Fat-laden hepatocytes may compromise sinusoid microcirculation leading to entrapment of inflammatory cells. Finally, steatosis may shift away Kupffer cells from alternative activation. Please see details in the text. Solid lines, pro-inflammatory effects; dotted lines, anti-inflammatory mechanisms. Malfunction at one or more steps may promote ‘second hit’ responses, while cellular targeting of these checkpoints has the potential for identifying novel treatment strategies in NAFLD.