The critical role of PPAR? in the binary switch between life and death induced by endoplasmic reticulum stress.
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ABSTRACT: 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? 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? and autophagy was significantly activated in the early stage but was inhibited in the late stage. Moreover, PPAR? inhibition by siRNA promoted cell injury in the mild-ER stress and PPAR? activation by WY-14643 reduced cell apoptosis in the serious ER stress. In the mild-ER stress with PPAR? knocked down, activation of autophagy by rapamycin significantly improved cell survival, in the serious ER stress with PPAR? activation, inhibition of autophagy by 3-MA aggravate cell injury. In addition, in the mild-ER stress with PPAR? knocked down, CHOP knocked down by siRNA reduced cell apoptosis, in the serious ER stress activated PPAR?, 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? 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? is a key molecule in the functional conversion of ER stress: protective effects in the mild ER stress was mediated by PPAR?-autophagy pathway and destructive effects in the serious ER stress was mediated by PPAR?-CHOP pathway.
SUBMITTER: Xu L
PROVIDER: S-EPMC7443130 | biostudies-literature | 2020 Aug
REPOSITORIES: biostudies-literature
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