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

Abstract

Non-alcoholic fatty liver disease (NAFLD) has become the most common liver disorder of our times. Simple steatosis, a seemingly innocent manifestation of NAFLD, may progress into steatohepatitis and cirrhosis, but this process is not well understood. Since NAFLD is associated with obesity and insulin resistance, mechanisms that link lipid metabolism to inflammation offer insights into the pathogenesis. An important parallel between obesity-related pathology of adipose tissue and liver pertains to the emerging role of macrophages and evidence is growing that Kupffer cells critically contribute to progression of NAFLD. Toll-like receptors, in particular TLR4, represent a major conduit for danger recognition linked to Kupffer cell activation and this process may be perturbed at multiple steps in NAFLD. Steatosis may interfere with sinusoid microcirculation and hepatocellular clearance of microbial and host-derived danger signals, enhancing responsiveness of Kupffer cells. Altered lipid homeostasis in NAFLD may unfavourably affect TLR4 receptor complex assembly and sorting, interfere with signalling flux redistribution, promote amplification loops, and impair negative regulation including alternative activation of Kupffer cells. These events are further promoted by altered adipokine secretion and reactive oxygen species production. Specific targeting of these interactions may provide more effective strategies in the treatment of NAFLD.

Figure 1. 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.