Abstract Body: Recent research on neurodegenerative diseases has highlighted a pathophysiological cascade characterized by abnormal lipid accumulation within the brain. Although progress has been made, the role of lipid metabolism following stroke remains unclear. This study aims to further explore changes in lipid metabolism after stroke, with a specific focus on the endoplasmic reticulum transmembrane protein 97 (TMEM97), which has emerged as a promising therapeutic target due to its critical role in cholesterol metabolism.
Spatial transcriptomic analyses following experimental stroke induction in mice revealed neuronal upregulation of crucial genes involved in lipid metabolism pathways, including LDLR, acetyl-CoA acetyltransferase 1, and elongation of very long-chain fatty acids protein 6, indicating dynamic adaptations post-stroke or under cellular stressors.
Initial findings demonstrate TMEM97 expression predominantly within neurons in vivo (mouse model). In an in vitro model of lipid starvation using mouse neural progenitor cells (MNPCs), pharmacological inhibition of lysosomal lipid release leads to increased expression of TMEM97. Interestingly, when TMEM97 was knocked down in MNPCs using lentiviral shRNA transfection, these cells exhibited no significant difference in neutral lipid accumulation compared to control cells. However, upon treatment with the lysosomal lipid release inhibitor, a significant increase in neutral lipid accumulation was observed exclusively in the TMEM97 knockdown cells.
Furthermore, Thapsigargin-induced endoplasmic reticulum (ER) stress in the MNPCs reduced TMEM97 expression, while also increasing low-density lipoprotein (LDL) uptake and the mRNA levels of the LDL receptor (LDLR). The observed elevation of neuronal LDLR expression in vitro closely aligns with the heightened expression of LDLR in vivo, suggesting a coordinated modulation of lipid metabolism pathways triggered by ER stress in response to stroke or metabolic stress induction. This synchronous upregulation of LDLR underscores the crucial role of ER stress as a potential trigger for this regulatory response. Additionally, considering the known involvement of TMEM97 in lipid homeostasis within the ER, it further highlights the intricate interplay between these proteins in post-stroke lipid metabolism regulation.
Our findings provide a compelling starting point for further exploring TMEM97's significance in post-ischemic lipid homeostasis.