Abstract

Endoplasmic reticulum stress (ER stress) plays a main role in pancreatic β -cell dysfunction and death because of intracellular Ca 2 + turbulence and inflammation activation. Although several drugs are targeting pancreatic β -cell to improve β -cell function, there still lacks agents to alleviate β -cell ER stress conditions. Therefore we used thapsigargin (THAP) or high glucose (HG) to induce ER stress in β -cell and aimed to screen natural molecules against ER stress-induced β -cell dysfunction. Through screening the Traditional Chinese drug library ( ∼ 1 0 0 0 molecules), luteolin was finally discovered to improve β -cell function. Cellular viability results indicated luteolin reduced the THAP or HG-induced β -cell death and apoptosis through MTT and flow cytometry assay. Moreover, luteolin improved β -cell insulin secretion ability under ER stress conditions. Also ER stress-induced intracellular Ca 2 + turbulence and inflammation activation were inhibited by luteolin treatment. Mechanically, luteolin inhibited HNF4 α signaling, which was induced by ER stress. Moreover, luteolin reduced the transcriptional level of HNF4 α downstream gene, such as Asnk4b and HNF1 α . Conversely HNF4 α knockdown abolished the effect of luteolin on β -cell using siRNA. These results suggested the protective effect of luteolin on β -cell was through HNF4 α /Asnk4b pathway. In conclusion, our study discovered that luteolin improved β -cell function and disclosed the underlying mechanism of luteolin on β -cell, suggesting luteolin is a promising agent against pancreatic dysfunction.