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KEAP the balance between life and death
Sophie C Cazanave1, Arun J Sanyal1
1Department of Internal Medicine, Division of Gastroenterology, Hepatology and Nutrition; Virginia Commonwealth University School of Medicine ; Richmond, VA USA.
Molecular & Cellular Oncology
|June 17, 2016
Summary
Cellular degradation of Kelch-like ECH-associated protein 1 (KEAP1) via autophagy promotes liver cell death. This process, linked to non-alcoholic fatty liver disease (NAFLD) and oxidative stress, may drive liver tumorigenesis.
Area of Science:
- Hepatology
- Molecular Biology
- Cancer Research
Background:
- Oxidative stress and hepatocyte apoptosis are key factors in non-alcoholic fatty liver disease (NAFLD) tumor development.
- Understanding the molecular mechanisms of liver cell death is crucial for NAFLD progression and tumorigenesis.
Purpose of the Study:
- To investigate the role of Kelch-like ECH-associated protein 1 (KEAP1) degradation in hepatocyte apoptosis.
- To elucidate the signaling pathways involved in KEAP1-mediated liver cell death.
Main Methods:
- Utilized autophagy-dependent degradation of KEAP1 via sequestrosome (SQSTM)1/p62.
- Analyzed the activation of c-Jun NH2 terminal kinase (JNK) pathway.
- Measured the expression of apoptosis-related proteins, including Bcl-2-interacting mediator (BIM) and p53 upregulated modulator of apoptosis (PUMA).
Main Results:
- Cellular degradation of KEAP1 through SQSTM1/p62-dependent autophagy activates JNK signaling.
- This process upregulates BIM and PUMA, promoting hepatocyte apoptosis induced by saturated free fatty acids.
- Demonstrated a direct link between KEAP1 degradation and apoptosis.
Conclusions:
- KEAP1 degradation is a critical mediator of hepatocyte apoptosis in response to saturated fatty acids.
- Dysregulation of KEAP1 may contribute to liver cell death and tumorigenesis in chronic inflammatory liver diseases like NAFLD.
- Targeting KEAP1 degradation pathways could offer therapeutic strategies for NAFLD-associated liver cancer.
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