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Aberrant hepatic TRIB3 gene expression in insulin-resistant obese humans

H Oberkofler1, A Pfeifenberger, S Soyal

  • 1Department of Laboratory Medicine, Landeskliniken and Paracelsus Private Medical University Salzburg, Müllner Hauptstr. 48, Salzburg, Austria. h.oberkofler@salk.at

Diabetologia
|May 13, 2010
PubMed
Abstract

Insights

Elevated hepatic TRIB3 (tribbles homologue 3) mRNA levels are linked to insulin resistance in obese humans. This study identifies potential gene regulation pathways for TRIB3 in the liver, offering insights into metabolic disease.

Area of Science:

  • Molecular biology
  • Human physiology
  • Metabolic research

Background:

  • Tribbles homologue 3 (Drosophila) (TRIB3) inhibits insulin signaling by interfering with v-akt murine thymoma viral oncogene homologue 1 (AKT1) phosphorylation.
  • Animal studies indicate increased TRIB3 expression during fasting and in diabetes models, potentially exacerbating hyperglycemia via enhanced hepatic glucose production.
  • Human data on TRIB3's role in insulin resistance is limited, though a gain-of-function mutation linked to insulin resistance has been reported.

Purpose of the Study:

  • To investigate the association between hepatic TRIB3 mRNA expression and insulin resistance in obese humans.
  • To identify potential transcriptional pathways regulating TRIB3 gene expression in the liver.

Main Methods:

  • Quantification of hepatic TRIB3 mRNA and key glucose homeostasis gene expression in obese patients with varying insulin resistance.
  • Assessment of biochemical variables related to intermediary metabolism.
  • In vitro analysis of TRIB3 promoter activity in HepG2 cells using specific nuclear receptor ligands and coactivators.

Main Results:

  • Hepatic TRIB3 mRNA expression correlated significantly with surrogate markers of insulin resistance in the study population.
  • A subgroup with high HOMA of insulin resistance (HOMA-IR) exhibited significantly increased TRIB3 mRNA levels compared to a low HOMA-IR group.
  • TRIB3 transcript levels showed positive correlations with mRNA expression of key metabolic regulators including PEPCK, PPARGC1A, PPARGC1B, USF1, FOXO1, and SREBP-1c.
  • Peroxisome proliferator-activated receptor alpha/retinoid X receptor pathway activation and overexpression of PPARGC1A, SREBP-1c, and PPARGC1B enhanced TRIB3 promoter activity in HepG2 cells.

Conclusions:

  • Aberrant hepatic TRIB3 transcript levels are implicated in insulin resistance among obese humans.
  • Potential transcriptional pathways, including those involving PPARGC1A, PPARGC1B, and SREBP-1c, are identified as regulators of TRIB3 gene expression in the liver.

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