The peroxisome proliferator-activated receptor (PPAR) β/δ agonist GW501516 inhibits IL-6-induced signal transducer and activator of transcription 3 (STAT3) activation and insulin resistance in human liver cells.

Abstract

AIM/HYPOTHESIS:

IL-6 induces insulin resistance by activating signal transducer and activator of transcription 3 (STAT3) and upregulating the transcription of its target gene SOCS3. Here we examined whether the peroxisome proliferator-activated receptor (PPAR)β/δ agonist GW501516 prevented activation of the IL-6-STAT3-suppressor of cytokine signalling 3 (SOCS3) pathway and insulin resistance in human hepatic HepG2 cells.

METHODS:

Studies were conducted with human HepG2 cells and livers from mice null for Pparβ/δ (also known as Ppard) and wild-type mice.

RESULTS:

GW501516 prevented IL-6-dependent reduction in insulin-stimulated v-akt murine thymoma viral oncogene homologue 1 (AKT) phosphorylation and in IRS-1 and IRS-2 protein levels. In addition, treatment with this drug abolished IL-6-induced STAT3 phosphorylation of Tyr⁷⁰⁵ and Ser⁷²⁷ and prevented the increase in SOCS3 caused by this cytokine. Moreover, GW501516 prevented IL-6-dependent induction of extracellular-related kinase 1/2 (ERK1/2), a serine-threonine protein kinase involved in serine STAT3 phosphorylation; the livers of Pparβ/δ-null mice showed increased Tyr⁷⁰⁵- and Ser⁷²⁷-STAT3 as well as phospho-ERK1/2 levels. Furthermore, drug treatment prevented the IL-6-dependent reduction in phosphorylated AMP-activated protein kinase (AMPK), a kinase reported to inhibit STAT3 phosphorylation on Tyr⁷⁰⁵. In agreement with the recovery in phospho-AMPK levels observed following GW501516 treatment, this drug increased the AMP/ATP ratio and decreased the ATP/ADP ratio.

CONCLUSIONS/INTERPRETATION:

Overall, our findings show that the PPARβ/δ activator GW501516 prevents IL-6-induced STAT3 activation by inhibiting ERK1/2 phosphorylation and preventing the reduction in phospho-AMPK levels. These effects of GW501516 may contribute to the prevention of cytokine-induced insulin resistance in hepatic cells.

• Authors: L Serrano-Marco, E Barroso, I El Kochairi, X Palomer, L Michalik, W Wahli, M Vázquez-Carrera
• Journal: Diabetologia (Diabetologia) Vol. 55 Issue 3 Pg. 743-51 (Mar 2012) ISSN: 1432-0428 [Electronic] Germany
• PMID: 22179221 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• GW 501516
• Interleukin-6
• PPAR delta
• PPAR-beta
• RNA, Messenger
• SOCS3 protein, human
• STAT3 Transcription Factor
• STAT3 protein, human
• Suppressor of Cytokine Signaling 3 Protein
• Suppressor of Cytokine Signaling Proteins
• Thiazoles

Topics

• Animals
• Cell Nucleus (drug effects, metabolism)
• Gene Expression Regulation (drug effects)
• Hep G2 Cells
• Hepatocytes (drug effects, metabolism)
• Humans
• Insulin Resistance
• Interleukin-6 (antagonists & inhibitors, metabolism)
• Male
• Mice
• Mice, Knockout
• PPAR delta (agonists, genetics, metabolism)
• PPAR-beta (agonists, genetics, metabolism)
• Phosphorylation (drug effects)
• Protein Processing, Post-Translational (drug effects)
• Protein Transport (drug effects)
• RNA, Messenger (metabolism)
• STAT3 Transcription Factor (antagonists & inhibitors, genetics, metabolism)
• Signal Transduction (drug effects)
• Suppressor of Cytokine Signaling 3 Protein
• Suppressor of Cytokine Signaling Proteins (genetics, metabolism)
• Thiazoles (pharmacology)