The inhibition of FKBP5 protects β-cell survival under inflammation stress via AKT/FOXO1 signaling

作者：Na Liu, Rui Li, Jinglin Cao, Xinyao Song, Wenmiao Ma, Tengli Liu, Le Wang, Jiaqi Zou, Boya Zhang, Zewen Liu, Rui Liang, Rongxiu Zheng, Shusen Wang · 发表于：Cell Death Discovery · 年份：2023 · DOI：10.1038/s41420-023-01506-x · 被引用次数：24 · 研究领域：Medicine

The FK506-binding protein 51 is expressed in human β cells. FKBP5 inhibition protects β-cell survival under inflammation stress. FOXO1 is the key downstream effector to mediate FKBP5 functioning in β cells. FKBP5 is downregulated in T2D, which may indicate a FKBP5-inhibition-mediated pro-survival mechanism. The FK506-binding protein 51 (FKBP51, encoded by FKBP5 gene) has emerged as a critical regulator of mammalian endocrine stress responses and as a potential pharmacological target for metabolic disorders, including type 2 diabetes (T2D). However, in β cells, which secrete the only glucose-lowering hormone—insulin, the expression and function of FKBP5 has not been documented. Here, using human pancreatic tissue and primary human islets, we demonstrated the abundant expression of FKBP5 in β cells, which displayed an responsive induction upon acute inflammatory stress mimicked by in vitro treatment with a cocktail of inflammatory cytokines (IL-1β, IFN-γ, and TNF-α). To explore its function, siRNAs targeting FKBP5 and pharmacological inhibitor SAFit2 were applied both in clonal NIT-1 cells and primary human/mice islets. We found that FKBP5 inhibition promoted β-cell survival, improved insulin secretion, and upregulated β-cell functional gene expressions ( MAFA and NKX6.1 ) in acute-inflammation stressed β cells. In primary human and mice islets, which constitutively suffer from inflammation stress during isolation and culture, FKBP5 inhibition also presented decent performance ...