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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
PubMed

Insights

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.
Keywords:
KEAP1Nrf2c-Jun NH2 terminal kinasehepatocyte lipoapoptosisliver cancer

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