Microglial SREBP2 regulate cholesterol-related lipid metabolism and inflammatory levels following ischemic stroke via the autophagy pathway.

BACKGROUND

Dysregulated lipid metabolism and inflammation exacerbate brain injury, with abnormal cholesterol metabolism playing a role in stroke condition. SREBPs are key transcription factors regulating lipid synthesis, and their activation is linked to autophagy. It remains unclear whether autophagy clears lipids and modulates inflammation after ischemic stroke, and whether SREBP2 affect cholesterol metabolism and inflammation via autophagy. This study aims to investigate the role of SREBPs and the mediating mechanism of autophagy in post-ischemic stroke lipid dysregulation and inflammation.

METHODS

In vivo mice models of ischemic stroke (middle cerebral artery occlusion, MCAO) and in vitro neuronal oxygen-glucose deprivation/reoxygenation (OGD/R) models were employed. Through interfering with SREBP2, combined with autophagy inhibitor/activator treatment, we detected cholesterol and cholesteryl ester in microglia and brain tissue, the expression levels of inflammatory factors, and the expression changes of autophagy-related proteins (LC3, p62) and SREBP downstream lipid metabolism-related genes.

RESULTS

After ischemic stroke, the expression of SREBP2 in brain tissue was significantly upregulated, the autophagy pathway was activated, accompanied by cholesterol and lipid accumulation and increased expression of inflammatory factors. Interfering with SREBP2 expression significantly inhibited the excessive activation of the autophagy pathway, reduced the content of cholesterol-related lipids in brain tissue and neurons, decreased the release of inflammatory factors, and alleviated cerebral ischemia-reperfusion injury. In microglia-neuron co-culture experiments, SREBPs interference in microglia significantly improved the survival rate of OGD/R-induced injured neurons and reduced neuronal apoptosis, while behavioral tests revealed that SREBP2 interference remarkably promoted neural function recovery in MCAO mice.

CONCLUSION

SREBP2 regulate the autophagy pathway to affect the balance of cholesterol-related lipid metabolism and the intensity of inflammatory responses after ischemic stroke, thereby participating in the pathophysiological process of cerebral ischemic injury, which provides a new target and theoretical basis for the treatment of ischemic stroke.