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Inflamm Res. 2012 Apr;61(4):349-58. doi: 10.1007/s00011-011-0417-3. Epub 2012 Jan 6.

FOXO1 involvement in insulin resistance-related pro-inflammatory cytokine production in hepatocytes.

Author information

1
Department of Biochemistry and Molecular Biology, The Third Military Medical University, Chongqing 400038, China. hongming.miao@gmail.com

Abstract

OBJECTIVE:

Low-grade inflammation from hepatocytes plays a causal role in hepatic and systemic insulin resistance (IR). We aimed to explore whether and how FOXO1 was involved in IR-related inflammation in hepatocytes.

METHODS:

We determined FOXO1 expression and activity, insulin and NF-κB signaling, and pro-inflammatory cytokine production in tumor necrosis factor-α (TNF-α)- or dexamethasone (DEX)-induced IR model in vitro and in high fat diet-induced obese or diabetic db/db mice in vivo with quantitative RT-PCR and Western blotting.

RESULTS:

We identified two different but physiologically relevant IR models characterized by attenuated insulin-induced phosphorylation of insulin receptor substrate-1 and AKT in TNF-α- or DEX-treated HepG2 cells. DEX largely increased FOXO1 expression in hepatocytes, while TNF-α did not. Notably, FOXO1 phosphorylation was attenuated in both models. TNF-α-stimulated nuclear translocation of NF-κB (p65) and mRNA levels of interleukin (IL)-1, IL-6 and monocyte attractant protein-1 were partly blocked, while the anti-inflammatory role of DEX was largely potentiated by insulin. FOXO1 knockdown by human-specific FOXO1 small interfering RNA exerted an identical role to insulin. Furthermore, augmented hepatic FOXO1 expression and decreased phosphorylation were found to be associated with elevated pro-inflammatory cytokine production in high fat diet-induced obese and db/db mice.

CONCLUSION:

FOXO1 potentiates pro-inflammatory cytokine production in insulin-resistant hepatocytes.

PMID:
22223069
DOI:
10.1007/s00011-011-0417-3
[Indexed for MEDLINE]

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