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Maladaptive regeneration — the reawakening of developmental pathways in NASH and fibrosis

Nature Reviews Gastroenterology & Hepatology volume 18, pages 131–142 (2021)Cite this article

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Abstract

With the rapid expansion of the obesity epidemic, nonalcoholic fatty liver disease is now the most common chronic liver disease, with almost 25% global prevalence. Nonalcoholic fatty liver disease ranges in severity from simple steatosis, a benign ‘pre-disease’ state, to the liver injury and inflammation that characterize nonalcoholic steatohepatitis (NASH), which in turn predisposes individuals to liver fibrosis. Fibrosis is the major determinant of clinical outcomes in patients with NASH and is associated with increased risks of cirrhosis and hepatocellular carcinoma. NASH has no approved therapies, and liver fibrosis shows poor response to existing pharmacotherapy, in part due to an incomplete understanding of the underlying pathophysiology. Patient and mouse data have shown that NASH is associated with the activation of developmental pathways: Notch, Hedgehog and Hippo–YAP–TAZ. Although these evolutionarily conserved fundamental signals are known to determine liver morphogenesis during development, new data have shown a coordinated and causal role for these pathways in the liver injury response, which becomes maladaptive during obesity-associated chronic liver disease. In this Review, we discuss the aetiology of this reactivation of developmental pathways and review the cell-autonomous and cell-non-autonomous mechanisms by which developmental pathways influence disease progression. Finally, we discuss the potential prognostic and therapeutic implications of these data for NASH and liver fibrosis.

Key points

  • Nonalcoholic steatohepatitis (NASH), defined as liver lipid accumulation accompanied by injury and inflammation, is a prevalent condition without approved pharmacotherapy, leading to huge unmet needs for an increasingly obese population.

  • Developmental pathways, including Notch, Hedgehog, Hippo–YAP–TAZ and WNT–β-catenin, are fundamental regulators of cell fate decisions and morphogenesis in liver development.

  • Developmental pathways are also activated to promote regenerative proliferation and/or cellular reprogramming in response to liver injury.

  • In the face of chronic liver disease such as NASH, persistent and maladaptive activation of developmental pathways leads to exacerbated NASH, fibrosis and liver cancer.

  • Inhibitors targeting developmental pathways can ameliorate NASH and fibrosis in preclinical models, uncovering novel therapeutic possibilities for patients with NASH.

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Fig. 1: Overview of developmental pathways in mammalian cells.
Fig. 2: A network of developmental signalling controls lineage commitment during mouse liver development.
Fig. 3: Cellular reprogramming during mouse liver regeneration.
Fig. 4: Pathogenesis of NASH and fibrosis in mouse models.
Fig. 5: The role of developmental pathways in liver cancer.

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Acknowledgements

The authors of this work were supported by the American Heart Association (17PRE33120000, to C.Z.) and the NIH (R01 DK103818 and R01 DK119767, to U.B.P.).

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  1. Changyu Zhu

    Present address: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA

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  1. Department of Medicine, Columbia University, New York, NY, USA

    Changyu Zhu, Ira Tabas, Robert F. Schwabe & Utpal B. Pajvani

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C.Z. researched data and literature for the article, made a substantial contribution to the discussion of content, wrote the article, and reviewed/edited the manuscript before submission. U.B.P. made a substantial contribution to the discussion of content, wrote the article and reviewed/edited the manuscript before submission. I.T. and R.F.S. made a substantial contribution to the discussion of content and reviewed the manuscript before submission.

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Zhu, C., Tabas, I., Schwabe, R.F. et al. Maladaptive regeneration — the reawakening of developmental pathways in NASH and fibrosis. Nat Rev Gastroenterol Hepatol 18, 131–142 (2021). https://doi.org/10.1038/s41575-020-00365-6

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