The critical role of PPARα in the binary switch between life and death induced by endoplasmic reticulum stress

Endoplasmic reticulum stress (ER stress) just like a double-edged sword depending on different conditions in the development of multiple hepatic diseases. But the molecular mechanisms of functional conversion during ER stress have not been fully elucidated. In this study, we aim to illustrate the role of PPAR alpha and the subtle mechanism in the functional conversion of ER stress. Tunicamycin (TM) and thapsigargin (TG), as ER stress inducers, were used to induce ER stress in AML12 cells. During the ER stress, qRT-PCR and immunoblotting was used to measure the expression levels of GRP78 and CHOP which show a gradually increasing trend, while PPAR alpha and autophagy was significantly activated in the early stage but was inhibited in the late stage. Moreover, PPAR alpha inhibition by siRNA promoted cell injury in the mild-ER stress and PPAR alpha activation by WY-14643 reduced cell apoptosis in the serious ER stress. In the mild-ER stress with PPAR alpha knocked down, activation of autophagy by rapamycin significantly improved cell survival, in the serious ER stress with PPAR alpha activation, inhibition of autophagy by 3-MA aggravate cell injury. In addition, in the mild-ER stress with PPAR alpha knocked down, CHOP knocked down by siRNA reduced cell apoptosis, in the serious ER stress activated PPAR alpha, CHOP over-expression mediated by lentiviral vector contributed to serious cell injury. Furthermore, C57BL/6 mice was used to induce ER stress with TM intraperitoneal injection, PPAR alpha and autophagy was upregulated in the mild-ER stress while downregulated in the serious ER stress, measured by qRT-PCR and immunoblotting, further confirmed the finding in vitro. Our results firstly demonstrated that PPAR alpha is a key molecule in the functional conversion of ER stress: protective effects in the mild ER stress was mediated by PPAR alpha-autophagy pathway and destructive effects in the serious ER stress was mediated by PPAR alpha-CHOP pathway.