Elsevier

Journal of Hepatology

Volume 51, Issue 1, July 2009, Pages 212-223
Journal of Hepatology

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

https://doi.org/10.1016/j.jhep.2009.03.008Get rights and content
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open access

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.

Keywords

Steatohepatitis
Macrophages
Toll-like receptors
Adiponectin
Uncoupling protein

Abbreviations

DAMP
damage-associated molecular pattern
LPS
lipopolysaccharide
LXR
liver X receptor
NAFLD
non-alcoholic fatty liver disease
NASH
non-alcoholic steatohepatitis
PAMP
pathogen-associated molecular pattern
PPAR
peroxisome proliferator-activated receptor
ROS
reactive oxygen species
TLR
Toll-like receptor
UCP2
uncoupling protein-2

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The author declared that he does not have anything to disclose regarding conflict of interest with respect to this manuscript. This work was partly funded by a NIH grant DK 61890.