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


CONCLUSIONS
FOXO1 potentiates pro-inflammatory cytokine production in insulin-resistant hepatocytes.
Department of Biochemistry and Molecular Biology, The Third Military Medical University, Chongqing 400038, China. hongming.miao@gmail.com
Hongming
H
Miao
Yang
Y
Zhang
Zhongyan
Z
Lu
Qin
Q
Liu
Lixia
L
Gan
D002460:Cell Line; D016207:Cytokines / Q000235:genetics*; D003907:Dexamethasone; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism
D016207:Cytokines; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D012333:RNA, Messenger; D003907:Dexamethasone