A key component in the development from fatty liver to hepatocellular carcinoma (HCC) is the appearance of nonalcoholic steatohepatitis (NASH). The precise cellular processes that trigger the advancement of NASH towards HCC are not well understood. In 2018, three key papers were published that help us better understand these processes.
Key advances
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Endoplasmic reticulum (ER) stress contributes to hepatocellular carcinoma (HCC) that is driven by nonalcoholic steatohepatitis (NASH)5,6,7.
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Caspase 2, a non-apoptotic caspase, is activated by the IRE1α branch of ER stress and controls NASH by cleaving site-1 protease, which activates sterol regulatory element-binding proteins and results in NASH development5.
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Inhibiting Bax inhibitor 1 increases the activity of the IRE1α signalling branch of the ER stress response and results in NASH, but more importantly the phenotype can be reversed by treating Bax inhibitor 1 null mice with an IRE1α RNase activity inhibitor7.
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Another approach to treat NASH-driven HCC is the use of small molecules mimicking AMPK-mediated acetyl-CoA carboxylase (ACC) inhibition as ACC-activating mutations increase hepatic carcinogenesis6.
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Change history
05 January 2019
In the original version of this manuscript, the incorrect names for two proteins were given. S1P and S2P should have been defined as site-1 protease and site-2 protease. This has been corrected in the HTML and PDF versions of the manuscript.
References
Fu, S., Watkins, S. M. & Hotamisligil, G. S. The role of endoplasmic reticulum in hepatic lipid homeostasis and stress signaling. Cell Metab. 15, 623–634 (2012).
Febbraio, M. A. et al. Preclinical models for studying NASH-driven HCC: how useful are they? Cell Metab. https://doi.org/10.1016/j.cmet.2018.10.012 (2018).
Kanda, T. et al. Apoptosis and non-alcoholic fatty liver diseases. World J. Gastroenterol. 24, 2661–2672 (2018).
Ringelhan, M. et al. The immunology of hepatocellular carcinoma. Nat. Immunol. 19, 222–232 (2018).
Kim, J. Y. et al. ER stress drives lipogenesis and steatohepatitis via caspase-2 activation of S1P. Cell 175, 133–145 (2018).
Lally, J. S. V. et al. Inhibition of acetyl-CoA carboxylase by phosphorylation or the inhibitor ND-654 suppresses lipogenesis and hepatocellular carcinoma. Cell Metab. https://doi.org/10.1016/j.cmet.2018.08.020 (2018).
Lebeaupin, C. et al. Bax inhibitor-1 protects from nonalcoholic steatohepatitis by limiting inositol-requiring enzyme 1 alpha signaling in mice. Hepatology 68, 515–532 (2018).
Nakagawa, H. et al. ER stress cooperates with hypernutrition to trigger TNF-dependent spontaneous HCC development. Cancer Cell 26, 331–343 (2014).
Liang, J. Q. et al. Dietary cholesterol promotes steatohepatitis related hepatocellular carcinoma through dysregulated metabolism and calcium signaling. Nat. Commun. 9, 4490 (2018).
Brown, M. S. & Goldstein, J. L. The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 89, 331–340 (1997).
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Reibe, S., Febbraio, M.A. Relieving ER stress to target NASH-driven hepatocellular carcinoma. Nat Rev Endocrinol 15, 73–74 (2019). https://doi.org/10.1038/s41574-018-0145-7
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DOI: https://doi.org/10.1038/s41574-018-0145-7
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