The Inducible Degrader of Low-Density Lipoprotein Receptor (IDOL) Exacerbates Cerebral Ischemia/Reperfusion Injury by Down-regulating Low-Density Lipoprotein Receptor (LDLR) Expression in Mice
Description
Cerebral ischemia-reperfusion injury (CI/RI) refers to the secondary brain damage that occurs when ischemic brain tissue is restored to blood supply. It is one of the main causes of adult disability and death. The progression of CI/RI involves multiple pathological mechanisms, including lipid metabolism disorders. Studies have shown that the low-density lipoprotein receptor (LDLR) is crucial in regulating cholesterol metabolism. LDLR reduces cholesterol levels through receptor-mediated endocytosis. Low-density lipoprotein receptor degrading agent (IDOL) inhibits the uptake of low-density lipoprotein (LDL) by down-regulating the expression of LDLR, resulting in hypercholesterolemia. However, the mechanism by which the IDOL-LDLR axis is involved in cerebral CI/RI remains unclear. In this study, IDOL knockdown was achieved via intracranial injection of adeno-associated virus carrying shRNA targeting IDOL (AAV-shIDOL). The results showed that IDOL silencing significantly upregulated LDLR expression, reduced cholesterol and triglyceride levels in the brain, and alleviated cerebral infarction, neurological deficits, histopathological damage, and neuronal apoptosis induced by middle cerebral artery occlusion (MCAO), thereby exerting a neuroprotective effect in CI/RI.