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The role of ADAM17 during liver damage

Mazin Al-Salihi1,2, Anna Bornikoel1, Yuan Zhuang1

  • 1Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University, Universitätsstr. 1, D-40225 Düsseldorf, Germany.

Biological Chemistry
|June 30, 2021
PubMed

Insights

ADAM17 regulates key proteins in liver injury. Its deletion worsens liver damage, while its substrates like EGFR ligands aid recovery, highlighting ADAM17

Area of Science:

  • Hepatology
  • Molecular Biology
  • Cellular Signaling

Background:

  • ADAM17 is a metalloprotease regulating membrane proteins crucial in liver injury.
  • ADAM17 substrates include TNFα, EGFR ligands (AR, HB-EGF), IL-6R, and c-Met, impacting liver cell fate.
  • Inactive rhomboid proteins (iRhoms) influence ADAM17 function and are linked to liver damage.

Purpose of the Study:

  • To elucidate the complex role of ADAM17 in liver injury and regeneration.
  • To understand how ADAM17 substrates contribute to or protect against liver damage.
  • To investigate the involvement of iRhoms in ADAM17-mediated liver pathology.

Main Methods:

  • Analysis of ADAM17 substrate cleavage and function in liver injury models.
  • Investigation of hepatocyte-specific ADAM17 deletion effects on liver damage.
  • Examination of the impact of EGFR ligands and IL-6 signaling on liver recovery.

Main Results:

  • ADAM17 deletion exacerbates liver cell damage, particularly after CD95 stimulation.
  • EGFR ligands (AR, HB-EGF) demonstrate protective effects, preventing hepatocyte death and promoting proliferation.
  • IL-6 trans-signaling is vital for liver regeneration and mitigating damage.

Conclusions:

  • ADAM17 plays a central, multifaceted role in both the pathogenesis and resolution of liver injury.
  • Dysregulation of ADAM17 and its substrates significantly impacts liver cell survival, apoptosis, and regeneration.
  • Targeting ADAM17 or its pathways may offer therapeutic strategies for liver diseases.
Keywords:
ADAM17IL-6TNFiRhomliver damageregeneration

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