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METABOLIC LIVER DISEASE IN 2018

Relieving ER stress to target NASH-driven hepatocellular carcinoma

Nature Reviews Endocrinology volume 15, pages 73–74 (2019)Cite this article

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An Author Correction to this article was published on 05 January 2019

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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

  • Endoplasmic reticulum (ER) stress contributes to hepatocellular carcinoma (HCC) that is driven by nonalcoholic steatohepatitis (NASH)5,6,7.

  • 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.

  • 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.

  • 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.

One organ that is highly challenged by the current obesity pandemic is the liver. The hepatic endoplasmic reticulum (ER) is pivotal as it processes many aspects of lipid metabolism1 and is clearly linked to the development of hepatocellular carcinoma (HCC)2. The exact steps involved are poorly understood, but one hallmark of the path from simple steatosis to HCC is the development of nonalcoholic steatohepatitis (NASH), a severe form of nonalcoholic fatty liver disease (NAFLD) that is characterized by inflammation, hepatocyte ballooning and fibrosis. However, the precise cellular processes that trigger the advancement of NASH and the downstream development of HCC remain unclear. Apoptosis, immune cell infiltration, lipotoxicity, de novo lipogenesis, the microbiota and oxidative stress have been shown to activate ER stress, thereby contributing to the initiation of NASH-driven HCC3. It is of vital importance to define the cellular processes and pathways that lead to NASH-driven HCC as current treatments for HCC, such as the tyrosine kinase inhibitor sorafenib, are ineffective therapies, as they only extend median survival by a few weeks to months in a subset of patients4.

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Fig. 1: The spectrum of disease progression from a healthy liver to hepatocellular carcinoma due to lipid overload.

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.

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Authors and Affiliations

  1. Division of Diabetes & Metabolism, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia

    Saskia Reibe & Mark A. Febbraio

  2. Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia

    Mark A. Febbraio

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  1. Saskia Reibe
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Correspondence to Mark A. Febbraio.

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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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