PMID- 32826849 OWN - NLM STAT- MEDLINE DCOM- 20210420 LR - 20211204 IS - 2041-4889 (Electronic) VI - 11 IP - 8 DP - 2020 Aug 11 TI - The critical role of PPARalpha in the binary switch between life and death induced by endoplasmic reticulum stress. PG - 691 LID - 10.1038/s41419-020-02811-4 [doi] LID - 691 AB - 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 PPARalpha 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 PPARalpha and autophagy was significantly activated in the early stage but was inhibited in the late stage. Moreover, PPARalpha inhibition by siRNA promoted cell injury in the mild-ER stress and PPARalpha activation by WY-14643 reduced cell apoptosis in the serious ER stress. In the mild-ER stress with PPARalpha knocked down, activation of autophagy by rapamycin significantly improved cell survival, in the serious ER stress with PPARalpha activation, inhibition of autophagy by 3-MA aggravate cell injury. In addition, in the mild-ER stress with PPARalpha knocked down, CHOP knocked down by siRNA reduced cell apoptosis, in the serious ER stress activated PPARalpha, 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, PPARalpha 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 PPARalpha is a key molecule in the functional conversion of ER stress: protective effects in the mild ER stress was mediated by PPARalpha-autophagy pathway and destructive effects in the serious ER stress was mediated by PPARalpha-CHOP pathway. FAU - Xu, Ling AU - Xu L AUID- ORCID: 0000-0001-8446-4045 AD - Beijing Youan Hospital, Capital Medical University, No. 8, XitouTiao Road, Youwai Street, Fengtai District, Beijing, 100069, China. FAU - Zhang, Xiangying AU - Zhang X AD - Beijing Youan Hospital, Capital Medical University, No. 8, XitouTiao Road, Youwai Street, Fengtai District, Beijing, 100069, China. FAU - Tian, Yuan AU - Tian Y AD - Beijing Youan Hospital, Capital Medical University, No. 8, XitouTiao Road, Youwai Street, Fengtai District, Beijing, 100069, China. FAU - Fan, Zihao AU - Fan Z AD - Beijing Youan Hospital, Capital Medical University, No. 8, XitouTiao Road, Youwai Street, Fengtai District, Beijing, 100069, China. FAU - Li, Weihua AU - Li W AD - Beijing Youan Hospital, Capital Medical University, No. 8, XitouTiao Road, Youwai Street, Fengtai District, Beijing, 100069, China. FAU - Liu, Mei AU - Liu M AD - Beijing Youan Hospital, Capital Medical University, No. 8, XitouTiao Road, Youwai Street, Fengtai District, Beijing, 100069, China. FAU - Hu, Jianhua AU - Hu J AD - Beijing Youan Hospital, Capital Medical University, No. 8, XitouTiao Road, Youwai Street, Fengtai District, Beijing, 100069, China. FAU - Duan, Zhongping AU - Duan Z AD - Beijing Youan Hospital, Capital Medical University, No. 8, XitouTiao Road, Youwai Street, Fengtai District, Beijing, 100069, China. FAU - Jin, Ronghua AU - Jin R AD - Beijing Youan Hospital, Capital Medical University, No. 8, XitouTiao Road, Youwai Street, Fengtai District, Beijing, 100069, China. Jin_eagle@yahoo.com. FAU - Ren, Feng AU - Ren F AD - Beijing Youan Hospital, Capital Medical University, No. 8, XitouTiao Road, Youwai Street, Fengtai District, Beijing, 100069, China. renfeng7512@hotmail.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200811 PL - England TA - Cell Death Dis JT - Cell death & disease JID - 101524092 RN - 0 (Ddit3 protein, mouse) RN - 0 (Endoplasmic Reticulum Chaperone BiP) RN - 0 (Heat-Shock Proteins) RN - 0 (Hspa5 protein, mouse) RN - 0 (PPAR alpha) RN - 11089-65-9 (Tunicamycin) RN - 147336-12-7 (Transcription Factor CHOP) RN - 67526-95-8 (Thapsigargin) SB - IM MH - Animals MH - Apoptosis/drug effects MH - Autophagy/drug effects MH - Cell Line MH - Cell Survival/drug effects MH - Endoplasmic Reticulum/pathology/physiology MH - Endoplasmic Reticulum Chaperone BiP MH - Endoplasmic Reticulum Stress/drug effects/*physiology MH - Heat-Shock Proteins/analysis/metabolism MH - Mice MH - Mice, Inbred C57BL MH - PPAR alpha/*metabolism/physiology MH - Thapsigargin/pharmacology MH - Transcription Factor CHOP/analysis/metabolism MH - Tunicamycin/pharmacology PMC - PMC7443130 COIS- The authors declare that they have no conflict of interest. EDAT- 2020/08/23 06:00 MHDA- 2021/04/21 06:00 PMCR- 2020/08/11 CRDT- 2020/08/23 06:00 PHST- 2020/01/30 00:00 [received] PHST- 2020/07/14 00:00 [accepted] PHST- 2020/07/13 00:00 [revised] PHST- 2020/08/23 06:00 [entrez] PHST- 2020/08/23 06:00 [pubmed] PHST- 2021/04/21 06:00 [medline] PHST- 2020/08/11 00:00 [pmc-release] AID - 10.1038/s41419-020-02811-4 [pii] AID - 2811 [pii] AID - 10.1038/s41419-020-02811-4 [doi] PST - epublish SO - Cell Death Dis. 2020 Aug 11;11(8):691. doi: 10.1038/s41419-020-02811-4.