Induction of hepatic insulin resistance by IL-1β and inflammation via TF/PAR2 pathway

• 발행기관: 한국노년학회
• 저자명: Dae Hyun Kim Min Jo Kim Hye Jin An Eun Jin Bang Kyung Chul Park Sugyeong Ha Yeojin Park A Kyoung Lee Min Kyung Hyun Eun Kyeong Lee Hee Jin Jung Hae Young Chung
• 간행물 정보: 『한국노년학회 학술대회 논문집』2017년 한국노인과학학술대회, 269~269쪽, 전체 1쪽
• 주제분류: 사회과학 > 사회복지학
• 파일형태: PDF
• 발행일자: 2017.11.03

영문 초록

The role of FoxO has been proposed for its promotion of insulin resistance, gluconeogenesis and inflammation. However, FoxO is a pro-inflammatory transcription factor which is a key mediator of inflammatory cytokine generation such as IL-1β in liver. Furthermore, the correlation of FoxO6 in insulin resistance and age-related inflammation has not been fully explored. We now demonstrate whether relation to between insulin resistance and age-related inflammation is altered in FoxO6-Tg and FoxO6-KO mice, focusing on IL-1β-induced activation of tissue factor (TF) and proteinase-activated receptor 2 (PAR2) in aging and diabetes models. The main purpose of the present study was to elucidate mechanisms underlying the role of FoxO6 in TF/PAR2 signaling under potent pro-inflammatory conditions induced by IL-1β, leading to gluconeogenesis (PEPCK, G6Pase) in liver. However, in type 2 diabetes and aging models, TF/PAR2-mediated age-related inflammation was derived by activation of pro-inflammatory transcription factor AP-1 through MAPK (ERK and JNK) pathway. Using a transfection with FoxO6-overexpression virus and FoxO6-directed siRNA approach in HepG2 cells revealed that FoxO6 binds to IRE-binding elements in the IL-1β promoter region, leading to IL-1β expression through AP-1 activation through ERK/JNK signaling and age-related inflammation (COX-2, iNOS) via TF/PAR2 pathways. Finally, PAR2 modulates insulin resistance and inflammation in FoxO6-KO, PAR2-siRNA-mediated knockdown, and PAR2-KO mice liver. Current study suggests FoxO6-induced IL-1β plays a pivotal role in the inflammatory response and hepatic insulin resistance through activated TF/PAR2 pathways in type 2 diabetes and aging models.

키워드

FoxO6 IL-1β TF/PAR2 signaling Inflammation Aging Insulin resistance