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

• Published in: Inflammation research Vol. 61; no. 4; pp. 349 - 358
• Main Authors: Miao, Hongming, Zhang, Yang, Lu, Zhongyan, Liu, Qin, Gan, Lixia
• Format: Journal Article
• Language: English
• Published: Basel SP Birkhäuser Verlag Basel 01.04.2012; Springer Nature B.V
• Subjects: AKT protein; Allergology; Animal models; Attractants; Biomedical and Life Sciences; Biomedicine; Cell Line; Cytokines; Cytokines - genetics; Dermatology; Dexamethasone; Diabetes mellitus; Forkhead Box Protein O1; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; FOXO1 protein; Gene Knockdown Techniques; Hepatocytes; Hepatocytes - metabolism; Humans; Immunology; Inflammation; Insulin; Insulin receptors; Insulin resistance; Insulin Resistance - physiology; Interleukin 6; Liver; Monocytes; mRNA; Neurology; NF- Kappa B protein; Nuclear transport; Obesity; Original Research Paper; Pharmacology/Toxicology; Phosphorylation; Polymerase chain reaction; Rheumatology; RNA, Messenger - metabolism; siRNA; Tumor necrosis factor- alpha; Western blotting; Low-grade inflammation; Insulin resistance; Hepatocyte; FOXO1
• ISSN: 1023-3830; 1420-908X
• DOI: 10.1007/s00011-011-0417-3

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.