SREBP1 deficiency diminishes glutamate-mediated HT22 cell damage and hippocampal neuronal pyroptosis induced by status epilepticus

Xing Ye; Jun-Yi Lin; Ling-Xia Chen; Xue-Chun Wu; Kai-Jun Ma; Bei-Xu Li; You-Xin Fang

doi:10.1016/j.heliyon.2023.e23945

SREBP1 deficiency diminishes glutamate-mediated HT22 cell damage and hippocampal neuronal pyroptosis induced by status epilepticus

Heliyon. 2023 Dec 18;10(1):e23945. doi: 10.1016/j.heliyon.2023.e23945. eCollection 2024 Jan 15.

Authors

Xing Ye^{1

2}, Jun-Yi Lin², Ling-Xia Chen³, Xue-Chun Wu⁴, Kai-Jun Ma⁵, Bei-Xu Li⁶, You-Xin Fang⁴

Affiliations

¹ Department of Forensic Medicine, School of Basic Medical Sciences, Gannan Medical University, Ganzhou, 341000, China.
² Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
³ Department of Pathogenic Biology, School of Basic Medical Sciences, Gannan Medical University, Ganzhou, 341000, China.
⁴ Department of Neurology, Minhang Hospital, Fudan University, Shanghai, China.
⁵ Shanghai Key Laboratory of Crime Scene Evidence, Institute of Forensic Science, Shanghai Public Security Bureau, Shanghai, 200083, China.
⁶ School of Policing Studies, Shanghai University of Political Science and Law, Shanghai, 201701, China.

Abstract

Status epilepticus (SE) is a life-threatening disorder that can result in death or severe brain damage, and there is a substantial body of evidence suggesting a strong association between pyroptosis and SE. Sterol regulatory element binding protein 1 (SREBP1) is a significant transcription factor participating in both lipid homeostasis and glucose metabolism. However, the function of SREBP1 in pyroptosis during SE remains unknown. In this study, we established a SE rat model by intraperitoneal injection of lithium chloride and pilocarpine in vivo. Additionally, we treated HT22 hippocampal cells with glutamate to create neuronal injury models in vitro. Our results demonstrated a significant induction of SREBP1, inflammasomes, and pyroptosis in the hippocampus of SE rats and glutamate-treated HT22 cells. Moreover, we found that SREBP1 is regulated by the mTOR signaling pathway, and inhibiting mTOR signaling contributed to the amelioration of SE-induced hippocampal neuron pyroptosis, accompanied by a reduction in SREBP1 expression. Furthermore, we conducted siRNA-mediated knockdown of SREBP1 in HT22 cells and observed a significant reversal of glutamate-induced cell death, activation of inflammasomes, and pyroptosis. Importantly, our confocal immunofluorescence analysis revealed the co-localization of SREBP1 and NLRP1. In conclusion, our findings suggest that deficiency of SREBP1 attenuates glutamate-induced HT22 cell injury and hippocampal neuronal pyroptosis in rats following SE. Targeting SREBP1 may hold promise as a therapeutic strategy for SE.

Keywords: NLRP1; Pyroptosis; SE; SREBP1.