Kupffer cells in non-alcoholic fatty liver disease: the emerging view.
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.
Baffy
György
G
Brigham and Women's Hospital and VA Boston Healthcare System, Harvard Medical School, Section of Gastroenterology, 150 S. Huntington Ave., Boston, MA 02130, USA. gbaffy@partners.org
D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000502:physiology; D005234:Fatty Liver / Q000209:etiology*; D006706:Homeostasis; D006801:Humans; D007728:Kupffer Cells / Q000502:physiology*; D050356:Lipid Metabolism; D008070:Lipopolysaccharides / Q000493:pharmacokinetics / Q000633:toxicity; D008262:Macrophage Activation; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000502:physiology; D054832:Urocortins / Q000502:physiology
D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; D051197:Toll-Like Receptor 4; C426705:UCN2 protein, human; D054832:Urocortins; D003346:Corticotropin-Releasing Hormone