FoxO6-mediated IL-1β induces hepatic insulin resistance and age-related inflammation via the TF/PAR2 pathway in aging and diabetic mice
| Autor: | Dae Hyun Kim, Bonggi Lee, Jaewon Lee, Mi Eun Kim, Jun Sik Lee, Jae Heun Chung, Byung Pal Yu, H. Henry Dong, Hae Young Chung |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: | |
| Zdroj: | Redox Biology, Vol 24, Iss , Pp - (2019) |
| Druh dokumentu: | article |
| ISSN: | 2213-2317 31744591 |
| DOI: | 10.1016/j.redox.2019.101184 |
| Popis: | FoxO has been proposed to play a role in the promotion of insulin resistance, and inflammation. FoxO is a pro-inflammatory transcription factor that is a key mediator of generation of inflammatory cytokines such as IL-1β in the liver. However, the detailed association of FoxO6 with insulin resistance and age-related inflammation has not been fully documented. Here, we showed that FoxO6 was elevated in the livers of aging rats and obese mice that exhibited insulin resistance. In addition, virus-mediated FoxO6 activation led to insulin resistance in mice with a notable increase in PAR2 and inflammatory signaling in the liver. On the other hand, FoxO6-KO mice showed reduced PAR2 signaling with a decrease in inflammatory cytokine expression and elevated insulin signaling. Because FoxO6 is closely associated with abnormal production of IL-1β in the liver, we focused on the FoxO6/IL-1β/PAR2 axis to further examine mechanisms underlying FoxO6-mediated insulin resistance and inflammation in the liver. In vitro experiments showed that FoxO6 directly binds to and elevates IL-1β expression. In turn, IL-1β treatment elevated the protein levels of PAR2 with a significant decrease in hepatic insulin signaling, whereas PAR2-siRNA treatment abolished these effects. However, PAR2-siRNA treatment had no effect on IL-1β expression induced by FoxO6, indicating that IL-1β may not be downstream of PAR2. Taken together, we assume that FoxO6-mediated IL-1β is involved in hepatic inflammation and insulin resistance via TF/PAR2 pathway in the liver. Keywords: FoxO6, IL-1β, TF/PAR2 signaling, Aging, Inflammation, Insulin resistance |
| Databáze: | Directory of Open Access Journals |
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