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Updated: Aug 7, 2026
07:54
Cholesterol Efflux Assay
Published on: March 6, 2012
Low cell cholesterol levels increase NFkappaB activity through a p38 MAPK-dependent mechanism
Laura Calleros1, Marina Lasa, María J Toro
1Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain.
Cellular Signalling
|June 30, 2006
Summary
Cholesterol depletion boosts NF-kappaB activity by activating p38 MAPK and MSK1, influencing both NF-kappaB nuclear translocation and its transcriptional potential. Restoring cholesterol levels reverses these effects.
Area of Science:
- Molecular Biology
- Cellular Signaling
- Biochemistry
Background:
- Cholesterol, p38 MAPK, and NF-kappaB are key regulators in inflammation and cellular differentiation.
- Previous research indicated that low cellular cholesterol activates the p38 MAPK pathway.
Purpose of the Study:
- To investigate the impact of cholesterol levels on NF-kappaB-dependent transcription in NIH3T3 cells.
- To elucidate the underlying molecular mechanisms connecting cholesterol, p38 MAPK, and NF-kappaB activation.
Main Methods:
- Cholesterol depletion using lipoprotein-deficient serum (LPDS) and 25-hydroxycholesterol (25-HC).
- Assessment of NF-kappaB-dependent transcription, DNA binding, IkappaBalpha degradation, and p65/NF-kappaB nuclear translocation.
- Pharmacological inhibition of p38 MAPK (SB203580) and MSK1 (H89), and genetic manipulation (MSK1 mutant, p65 S276A mutant).
Main Results:
- Cholesterol depletion significantly increased NF-kappaB activity, IkappaBalpha degradation, and p65/NF-kappaB nuclear translocation; exogenous cholesterol reversed these changes.
- Inhibition of p38 MAPK or MSK1 blocked cholesterol depletion-induced NF-kappaB activation.
- Cholesterol depletion enhanced p65/NF-kappaB transactivation potential via MSK1 phosphorylation of p65 at S276; a p65 S276A mutant was insensitive to cholesterol levels.
Conclusions:
- Cholesterol depletion activates NF-kappaB transcriptional activity through a p38 MAPK/MSK1 pathway.
- This pathway modulates both NF-kappaB nuclear translocation and its transactivation potential.
- Cellular cholesterol levels are critical regulators of NF-kappaB signaling.
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