The contribution of endoplasmic reticulum stress to liver diseases

Authors

  • Lily Dara,

    Corresponding author
    1. University of Southern California (USC) Research Center for Liver Diseases and the Division of Gastrointestinal and Liver Diseases, Keck School of Medicine of USC, Los Angeles, CA
    • M.D., USC Research Center for Liver Disease, 2011 Zonal Ave HMR 101, Los Angeles, CA 90033
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    • fax: 323-442-3243

  • Cheng Ji,

    1. University of Southern California (USC) Research Center for Liver Diseases and the Division of Gastrointestinal and Liver Diseases, Keck School of Medicine of USC, Los Angeles, CA
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  • Neil Kaplowitz

    1. University of Southern California (USC) Research Center for Liver Diseases and the Division of Gastrointestinal and Liver Diseases, Keck School of Medicine of USC, Los Angeles, CA
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  • Potential conflict of interest: Nothing to report.

  • This work was supported by National Institutes of Health grants RO1 DK067215 (N.K.), R01 AA018846 (to N.K., C.J.), R01 AA014428 (C.J.), and R01 AA018612 (C.J.) and the USC Research Center for Liver Disease (P30 DK48522) and the Southern California Research Center for Alcoholic Liver and Pancreas Disease (P50 AA11999).

Abstract

The unfolded protein response (UPR) is an evolutionarily conserved cell signaling pathway that is activated to regulate protein synthesis and restore homeostatic equilibrium when the cell is stressed from increased client protein load or the accumulation of unfolded or malfolded proteins. Once activated, this signaling pathway can either result in the recovery of homeostasis or can activate a cascade of events that ultimately result in cell death. The UPR/endoplasmic reticulum (ER) stress response spectrum and its interplay with other cellular organelles play an important role in the pathogenesis of disease in secretory cells rich in ER, such as hepatocytes. Over the past 2 decades, the contribution of ER stress to various forms of liver diseases has been examined. Robust support for a contributing, as opposed to a secondary role, for ER stress response is seen in the nonalcoholic steatohepatitis, alcoholic liver disease, ischemia/reperfusion injury, and cholestatic models of liver disease. The exact direction of the cause and effect relationship between modes of cell injury and ER stress remains elusive. It is apparent that a complex interplay exists between ER stress response, conditions that promote it, and those that result from it. A vicious cycle in which ER stress promotes inflammation, cell injury, and steatosis and in which steatogenesis, inflammation, and cell injury aggravate ER stress seems to be at play. It is perhaps the nature of such a vicious cycle that is the key pathophysiologic concept. Therapeutic approaches aimed at interrupting the cycle may dampen the stress response and the ensuing injury. (HEPATOLOGY 2011;)

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