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Endoplasmic reticulum stress in liver disease
Harmeet Malhi1, Randal J Kaufman
1Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic, Rochester, MN, USA.
Journal of Hepatology
|December 15, 2010
Summary
The unfolded protein response (UPR) helps cells adapt to endoplasmic reticulum (ER) stress by managing misfolded proteins. If stress persists, UPR failure can lead to liver disease and cell death, suggesting therapeutic potential.
Area of Science:
- Cellular Biology
- Molecular Biology
- Hepatology
Background:
- The unfolded protein response (UPR) is a cellular stress response pathway.
- Accumulation of misfolded proteins in the endoplasmic reticulum (ER) triggers the UPR.
- The UPR involves three main sensors: IRE1α, PERK, and ATF6α.
Purpose of the Study:
- To discuss the mechanisms of each UPR branch.
- To explore the role of UPR in liver diseases.
- To investigate the link between ER stress, steatosis, and hepatocyte apoptosis.
Main Methods:
- Review of UPR signaling pathways.
- Analysis of UPR activation in liver disease models.
- Discussion of therapeutic implications.
Main Results:
- PERK activation leads to eIF2α phosphorylation and ATF4/CHOP translation.
- IRE1α activation splices XBP1 mRNA and activates JNK.
- ATF6α activation results in a soluble transcription factor after Golgi cleavage.
- UPR pathways collectively enhance ER capacity and degrade misfolded proteins.
- Persistent ER stress can lead to apoptosis via CHOP, calcium, and ROS.
- UPR is implicated in liver diseases like fatty liver, hepatitis, and alcohol-induced injury, potentially linking ER stress to steatosis.
Conclusions:
- UPR activation is a key factor in hepatocyte function during liver disease.
- ER stress and UPR dysregulation contribute to steatosis and apoptosis in liver pathologies.
- Restoring ER homeostasis offers a potential therapeutic strategy for liver diseases associated with ER stress.
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