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.

Details

Serval ID
serval:BIB_E76280237723
Type
Article: article from journal or magazin.
Collection
Publications
Title
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.
Journal
Diabetologia
Author(s)
Serrano-Marco L., Barroso E., El Kochairi I., Palomer X., Michalik L., Wahli W., Vázquez-Carrera M.
ISSN
1432-0428 (Electronic)
ISSN-L
0012-186X
Publication state
Published
Issued date
2012
Volume
55
Number
3
Pages
743-751
Language
english
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.
Keywords
Animals, Cell Nucleus/drug effects, Cell Nucleus/metabolism, Gene Expression Regulation/drug effects, Hep G2 Cells, Hepatocytes/drug effects, Hepatocytes/metabolism, Humans, Insulin Resistance, Interleukin-6/antagonists & inhibitors, Interleukin-6/metabolism, Male, Mice, Mice, Knockout, PPAR delta/agonists, PPAR delta/genetics, PPAR-beta/agonists, PPAR-beta/genetics, Phosphorylation/drug effects, Protein Processing, Post-Translational/drug effects, Protein Transport/drug effects, RNA, Messenger/metabolism, STAT3 Transcription Factor/antagonists & inhibitors, STAT3 Transcription Factor/genetics, Signal Transduction/drug effects, Suppressor of Cytokine Signaling Proteins/genetics, Suppressor of Cytokine Signaling Proteins/metabolism, Thiazoles/pharmacology
Pubmed
Web of science
Open Access
Yes
Create date
06/03/2012 20:21
Last modification date
20/08/2019 17:10
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