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Tumor necrosis factor and interleukin 1 decrease RXRalpha, PPARalpha, PPARgamma, LXRalpha, and the coactivators

Min Sun Kim1, Trevor R Sweeney, Judy K Shigenaga

  • 1Department of Medicine, University of California San Francisco, San Francisco, CA 94143, USA.

Metabolism: Clinical and Experimental
|January 17, 2007
PubMed

Insights

Cytokines like TNF and IL-1 reduce key nuclear receptors and coactivators involved in lipid metabolism, contributing to altered liver function during the acute phase response.

Area of Science:

  • Molecular Biology
  • Metabolic Regulation
  • Cellular Signaling

Background:

  • Cytokines orchestrate the acute phase response, significantly impacting lipid metabolism.
  • Previous studies noted changes in serum triglycerides, fatty acid oxidation, bile acid synthesis, and HDL levels during this response.

Purpose of the Study:

  • To investigate the effect of specific cytokines, tumor necrosis factor (TNF) and interleukin 1 (IL-1), on the expression of nuclear hormone receptors and coactivators in hepatic cells.
  • To elucidate the molecular mechanisms underlying cytokine-induced alterations in hepatic lipid metabolism.

Main Methods:

  • Treatment of Hep3B human hepatoma cells and mice with TNF and IL-1.
  • Quantitative analysis of messenger RNA (mRNA) levels for retinoid X receptor alpha (RXRalpha), peroxisome proliferator-activated receptors (PPARalpha, PPARgamma), liver X receptor alpha (LXRalpha), and coactivators (PGC-1alpha, PGC-1beta, SRC-1).
  • Assessment of nuclear extract binding to response elements and luciferase reporter assays.
  • Measurement of mRNA levels for downstream target genes regulated by PPARalpha and LXR.
  • Analysis of promoter activity using luciferase constructs.

Main Results:

  • TNF and IL-1 significantly decreased the expression of RXRalpha, PPARalpha, PPARgamma, LXRalpha, PGC-1alpha, PGC-1beta, and SRC-1 in Hep3B cells and mouse liver.
  • These reductions were associated with decreased DNA binding activity and transcriptional activity of PPAR and LXR.
  • mRNA levels of key metabolic enzymes regulated by PPARalpha and LXR were also diminished.
  • Decreased transcription of LXRalpha and PGC-1alpha promoters was observed, indicating transcriptional downregulation.

Conclusions:

  • The study demonstrates that TNF and IL-1 suppress the expression of critical nuclear hormone receptors and coactivators in the liver.
  • This suppression, driven by decreased transcription, likely contributes to the altered hepatic lipid metabolism observed during the acute phase response.
  • Targeting these pathways could offer therapeutic strategies for managing metabolic dysregulation during inflammation.

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