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Endoplasmic reticulum proteostasis in hepatic steatosis

Nature Reviews Endocrinology volume 12, pages 710–722 (2016)Cite this article

Subjects

Key Points

  • Increased lipid content in the steatotic liver induces chronic endoplasmic reticulum (ER) stress, mainly via the alteration of Ca2+ homeostasis

  • Classic ER stress responses such as ER-associated degradation and the unfolded protein response take place to counteract ER stress

  • In the context of the fatty liver, autophagy is unlikely to contribute to the ER stress defence process

  • Rather than alleviating ER stress, aspects of the ER stress responses instead promote hepatocyte lipid accumulation and are, therefore, implicated in the progression of nonalcoholic liver disease.

Abstract

Hepatic steatosis, the first step in the progression of nonalcoholic fatty liver disease, is characterized by triglyceride accumulation in hepatocytes and is highly prevalent in people with obesity. Although initially asymptomatic, hepatic steatosis is an important risk factor for the development of hepatic insulin resistance and type 2 diabetes mellitus and can also progress to more severe pathologies such as nonalcoholic steatohepatitis, liver fibrosis and cirrhosis; hepatic steatosis has, therefore, received considerable research interest in the past 20 years. The lipid accumulation that defines hepatic steatosis disturbs the function of the endoplasmic reticulum (ER) in hepatocytes, thereby generating chronic ER stress that interferes with normal cellular function. Although ubiquitous stress response mechanisms (namely, ER-associated degradation, unfolded protein response and autophagy) are the main processes for restoring cellular proteostasis, these mechanisms are unable to alleviate ER stress in the context of the fatty liver. Furthermore, ER stress and ER stress responses can promote lipid accumulation in hepatocytes in a counter-productive manner and could, therefore, be the origin of a vicious pathological cycle.

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Figure 1: ER stress and associated lines of defence.
Figure 2: The unfolded protein response.
Figure 3: ER stress and hepatic steatosis: a vicious cycle.

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Acknowledgements

Work in the authors' laboratories is supported by INSERM, CNRS and the Fondation pour la Recherche Médicale (équipe FRM DEQ20140329504), France. P.M. is the recipient of a fellowship from the Institute of Cardiometabolism and Nutrition (ICAN), France. A.B. is supported by a scholarship from the Fondation Jacques Tacussel, France. We apologize to our colleagues whose work could not been cited owing to space limitations.

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  1. Institut National de la Santé et de la Recherche Médicale, UMRS 1138, Centre de Recherche des Cordeliers, Paris, F-75006, France

    Andrei Baiceanu, Pierre Mesdom, Marie Lagouge & Fabienne Foufelle

  2. Sorbonne Universités, UPMC Univ Paris 06, UMRS 1138, Centre de Recherche des Cordeliers, Paris, F-75006, France

    Andrei Baiceanu, Pierre Mesdom, Marie Lagouge & Fabienne Foufelle

  3. Université Paris Descartes, Sorbonne Paris Cité, UMRS 1138, Centre de Recherche des Cordeliers, 15 rue de l'école de médecine,, Paris, F-75006, France

    Andrei Baiceanu, Pierre Mesdom, Marie Lagouge & Fabienne Foufelle

  4. University of Medicine and Pharmacy Iuliu Hat¸ieganu, Faculty of Pharmacy, 8 Victor Babes Street, Cluj-Napoca, 400012, Romania

    Andrei Baiceanu

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All authors wrote and researched data for the article, M.L. and F.F. contributed substantially to the discussion of article content and reviewed and/or edited the manuscript before submission.

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Baiceanu, A., Mesdom, P., Lagouge, M. et al. Endoplasmic reticulum proteostasis in hepatic steatosis. Nat Rev Endocrinol 12, 710–722 (2016). https://doi.org/10.1038/nrendo.2016.124

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