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Cellular stress in the pathogenesis of nonalcoholic steatohepatitis and liver fibrosis

Nature Reviews Gastroenterology & Hepatology volume 20, pages 662–678 (2023)Cite this article

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Abstract

The burden of chronic liver disease is rising substantially worldwide. Fibrosis, characterized by excessive deposition of extracellular matrix proteins, is the common pathway leading to cirrhosis, and limited treatment options are available. There is increasing evidence suggesting the role of cellular stress responses contributing to fibrogenesis. This Review provides an overview of studies that analyse the role of cellular stress in different cell types involved in fibrogenesis, including hepatocytes, hepatic stellate cells, liver sinusoidal endothelial cells and macrophages.

Key points

  • Chronic activation of endoplasmic reticulum stress in hepatocytes drives nonalcoholic steatohepatitis (ΝASH) pathogenesis, insulin resistance, fat accumulation, inflammation, fibrogenesis and liver fibrosis through inadequate unfolded protein response, cell death and inflammation.

  • Mitochondrial dysfunction and oxidative stress drive NASH and liver fibrosis by causing hepatocyte damage, immune cell activation and inflammation.

  • Cellular stress pathways in hepatocytes also contribute to fibrogenesis independent of NASH.

  • Intracellular reactive oxygen species generation provokes endoplasmic reticulum stress and autophagy that contribute to the activation of hepatic stellate cells.

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Fig. 1: Overview of cell types in hepatic fibrosis.
Fig. 2: Overview of oxidative stress-activated pathways in NASH.
Fig. 3: Overview of cellular stress in hepatic stellate cells.
Fig. 4: Small molecules targeting each UPR branch.

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Author notes

  1. These authors contributed equally: Sachin Sharma, Dounia Le Guillou.

Authors and Affiliations

  1. Department of Medicine, University of California, San Francisco, San Francisco, CA, USA

    Sachin Sharma, Dounia Le Guillou & Jennifer Y. Chen

  2. The Liver Center, University of California, San Francisco, San Francisco, CA, USA

    Sachin Sharma, Dounia Le Guillou & Jennifer Y. Chen

Authors
  1. Sachin Sharma
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  2. Dounia Le Guillou
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  3. Jennifer Y. Chen
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The authors contributed equally to all aspects of the article.

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Correspondence to Jennifer Y. Chen.

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Nature Reviews Gastroenterology and Hepatology thanks Jun Ren, Ariel Feldstein and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Sharma, S., Le Guillou, D. & Chen, J.Y. Cellular stress in the pathogenesis of nonalcoholic steatohepatitis and liver fibrosis. Nat Rev Gastroenterol Hepatol 20, 662–678 (2023). https://doi.org/10.1038/s41575-023-00832-w

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