Downregulation of FLIP by cycloheximide sensitizes human fat cells to CD95-induced apoptosis

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Measuring Composition of CD95 Death-Inducing Signaling Complex and Processing of Procaspase-8 in this Complex
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Measuring Composition of CD95 Death-Inducing Signaling Complex and Processing of Procaspase-8 in this Complex

Published on: August 2, 2021

Pamela Fischer-Posovszky1, Michaela Keuper, Stella Nagel

  • 1Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, University of Ulm, Germany.

Experimental Cell Research
|July 16, 2011
PubMed

Insights

Inhibition of protein synthesis sensitizes fat cells to apoptosis by reducing FLICE-like inhibitory protein (FLIP). This mechanism, observed in human cells and fasting mice, highlights FLIP as a target for managing adipose tissue.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Metabolic Research

Background:

  • Adipocyte apoptosis regulates fat depot size.
  • Protein synthesis inhibition sensitizes human adipocytes to apoptosis.
  • Calorie restriction causes significant protein expression changes in fat cells.

Purpose of the Study:

  • To investigate the mechanism of death receptor-induced apoptosis sensitization in human preadipocytes and adipocytes.
  • To elucidate the role of protein synthesis inhibition in regulating apoptosis sensitivity.
  • To identify key molecular players involved in fat cell apoptosis.

Main Methods:

  • Treatment of human preadipocytes and adipocytes with cycloheximide (CHX).
  • Assessment of apoptosis using CD95 stimulation and caspase activity assays.
  • Analysis of pro- and anti-apoptotic protein expression, including FLICE-like inhibitory protein (FLIP).
  • RNA interference (shRNA) to down-regulate FLIP expression.
  • Measurement of adipose tissue Flip mRNA levels in fasting mice.

Main Results:

  • Cycloheximide (CHX) sensitized human fat cells to CD95-induced apoptosis in a caspase-dependent manner.
  • CHX treatment led to decreased expression of FLICE-like inhibitory protein (FLIP).
  • Reduced FLIP levels resulted in enhanced caspase-8 activation at the CD95 death-inducing signaling complex (DISC).
  • Down-regulation of FLIP sensitized preadipocytes to CD95-induced apoptosis.
  • Fasting in mice led to decreased adipose tissue Flip mRNA levels.

Conclusions:

  • FLICE-like inhibitory protein (FLIP) is a critical regulator of apoptosis sensitivity in fat cells.
  • Modulating adipocyte apoptosis via FLIP down-regulation offers a potential therapeutic strategy for excess adipose tissue.
  • Targeting FLIP may provide a novel approach for managing obesity and related metabolic disorders.

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