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NF-κB in the liver—linking injury, fibrosis and hepatocellular carcinoma

Abstract

Hepatic cirrhosis and hepatocellular carcinoma (HCC) are the most common causes of death in patients with chronic liver disease. Chronic liver injury of virtually any etiology triggers inflammatory and wound-healing responses that in the long run promote the development of hepatic fibrosis and HCC. Here, we review the role of the transcription factor nuclear factor-κB (NF-κB), a master regulator of inflammation and cell death, in the development of hepatocellular injury, liver fibrosis and HCC, with a particular focus on the role of NF-κB in different cellular compartments of the liver. We propose that NF-κB acts as a central link between hepatic injury, fibrosis and HCC, and that it may represent a target for the prevention or treatment of liver fibrosis and HCC. However, NF-κB acts as a two-edged sword and inhibition of NF-κB may not only exert beneficial effects but also negatively impact hepatocyte viability, especially when NF-κB inhibition is pronounced. Finding appropriate targets or identifying drugs that either exert only a moderate effect on NF-κB activity or that can be specifically delivered to nonparenchymal cells will be essential to avoid the increase in liver injury associated with complete NF-κB blockade in hepatocytes.

Key Points

  • Nuclear factor-κB (NF-κB) is a key regulator of inflammation in many hepatic cell populations and is required for hepatocyte survival and liver homeostasis

  • Survival and activation of hepatic stellate cells and hepatic myofibroblasts is regulated by NF-κB

  • The key roles of NF-κB in the regulation of cell death, inflammation and wound healing make it an important modulator of hepatic disease progression

  • NF-κB is a potential link between chronic liver injury, fibrosis and hepatocellular carcinoma

  • Cell-type-specific functions of NF-κB need to be taken into account when designing therapies that target this transcription factor

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Figure 1: Regulation of NF-κB activation, inflammation and apoptosis after TNF stimulation.
Figure 2: The contribution of NF-κB to hepatic stellate cell activation and survival.
Figure 3: NF-κB contributes to hepatocarcinogenesis in the setting of chronic injury, inflammation and fibrosis.

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Acknowledgements

The authors acknowledge the support of NIH grants U54CA126513, R01DK076920 and R21AT003878 (R. F. Schwabe), European Research Council Starting grant ERC-2007-Stg/208237 (T. Luedde), the German Research Foundation grant SFB/TRR57/P06 (T. Luedde) and an Ernst-Jung-Foundation (Hamburg) grant (T. Luedde).

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Luedde, T., Schwabe, R. NF-κB in the liver—linking injury, fibrosis and hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 8, 108–118 (2011). https://doi.org/10.1038/nrgastro.2010.213

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