Liver function and dysfunction – a unique window into the physiological reach of ER stress and the unfolded protein response

• Published in: The FEBS journal Vol. 286; no. 2; pp. 356 - 378
• Main Author: Rutkowski, D. Thomas
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.01.2019
• Subjects: alcoholic sort or nonalcoholic; Animals; diabetes; Endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum - pathology; Endoplasmic Reticulum Stress; Folding; hepatocellular carcinoma; Homeostasis; Humans; inflammation; insulin; lipid metabolism; Liver; Liver - physiology; Liver diseases; Liver Diseases - physiopathology; Metabolism; obesity; Physiology; Protein Folding; Proteins; Signal Transduction; Signaling; Stress; Tissues; Unfolded Protein Response; alcoholic sort or nonalcoholic; unfolded protein response; insulin; inflammation; lipid metabolism; diabetes; endoplasmic reticulum stress; hepatocellular carcinoma; obesity
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/febs.14389

The unfolded protein response (UPR) improves endoplasmic reticulum (ER) protein folding in order to alleviate stress. Yet it is becoming increasingly clear that the UPR regulates processes well beyond those directly involved in protein folding, in some cases by mechanisms that fall outside the realm of canonical UPR signaling. These pathways are highly specific from one cell type to another, implying that ER stress signaling affects each tissue in a unique way. Perhaps nowhere is this more evident than in the liver, which—beyond being a highly secretory tissue—is a key regulator of peripheral metabolism and a uniquely proliferative organ upon damage. The liver provides a powerful model system for exploring how and why the UPR extends its reach into physiological processes that occur outside the ER, and how ER stress contributes to the many systemic diseases that involve liver dysfunction. This review will highlight the ways in which the study of ER stress in the liver has expanded the view of the UPR to a response that is a key guardian of cellular homeostasis outside of just the narrow realm of ER protein folding. The unfolded protein response (UPR) restores endoplasmic reticulum homeostasis during stress. In the liver, the UPR is regulated by—and in turn contributes to—both metabolism and liver damage. This review highlights these connections and what they tell us about both the physiology and pathophysiology of the liver and the cell biology of the UPR.