Unfolded Protein Response Signaling in Liver Disorders: A 2023 Updated Review

Abstract

Endoplasmic reticulum (ER) is the site for synthesis and folding of secreted and transmembrane proteins. Disturbance in the functioning of ER leads to the accumulation of unfolded and misfolded proteins, which finally activate the unfolded protein response (UPR) signaling. The three branches of UPR—IRE1 (Inositol requiring enzyme 1), PERK (Protein kinase RNA-activated (PKR)-like ER kinase), and ATF6 (Activating transcription factor 6)—modulate the gene expression pattern through increased expression of chaperones and restore ER homeostasis by enhancing ER protein folding capacity. The liver is a central organ which performs a variety of functions which help in maintaining the overall well-being of our body. The liver plays many roles in cellular physiology, blood homeostasis, and detoxification, and is the main site at which protein synthesis occurs. Disturbance in ER homeostasis is triggered by calcium level imbalance, change in redox status, viral infection, and so on. ER dysfunction and subsequent UPR signaling participate in various hepatic disorders like metabolic (dysfunction) associated fatty liver disease, liver cancer, viral hepatitis, and cholestasis. The exact role of ER stress and UPR signaling in various liver diseases is not fully understood and needs further investigation. Targeting UPR signaling with drugs is the subject of intensive research for therapeutic use in liver diseases. The present review summarizes the role of UPR signaling in liver disorders and describes why UPR regulators are promising therapeutic targets.

Endoplasmic Reticulum Stress Induces Vasodilation in Liver Vessels That Is Not Mediated by Unfolded Protein Response

“…The frequent appearance of perfusion disorders affecting the liver may be explained by the fact that it has a unique dual blood supply, which originates from the hepatic artery (25%) and the portal vein (75%). Although impaired liver perfusion and ER stress often accompany each other, the exact impact of ER stress and UPR on the hepatic perfusion is not fully understood [12].…”

Long non‐coding RNA‐mediated modulation of endoplasmic reticulum stress under pathological conditions

“…Additionally, NASH also seems to be associated with the activation of the IRE1/JNK/NF-kB pathway. 114 Another interesting study reports that the ATF6 pathway of the UPR is inhibited and the IRE1 pathway is activated resulting in sXBP1 activation under normal conditions while the lack of insulin promotes the ATF6mediated activation of CHOP that could lead to cell death in diabetic nephropathy (DN). 90 Cancer cells display an elevated interest in ER stress because of the particular environment they inhabit, characterized by increased glucose deprivation and hypoxia.…”

Frontiers of Collaboration between Primary Care and Specialists in the Management of Metabolic Dysfunction-Associated Steatotic Liver Disease: A Review

“…ER stress promotes fatty acid synthesis by activating SREBP-1c, suppresses VLDL production by inhibiting translation and degradation of apoB-100, and enhances fat accumulation in hepatocytes. Therefore, at least part of the cellular damage caused by ER stress may occur through oxidative stress-mediated mechanisms [38,39].…”