IDOL Exacerbates Cerebral ischemia/reperfusion injury by down-regulating LDLR expression in mice

Abundant evidence has demonstrated a close association between cerebral ischemia-reperfusion injury (CI/RI) and elevated cholesterol levels in the brain . The LDLR protein plays a key role in regulating cholesterol levels . LDLR is not only an important therapeutic target for cardiovascular diseases but also a key target for the prevention and treatment of IS . Recent studies have confirmed that lipid-lowering therapy is one of the most important strategies for the treatment of CI/RI. Compared with that in wild-type mice, intracellular red blood cell accumulation, thrombus occlusion, BBB dysfunction, and microbleedings were observed in LDLR knockout mice . These findings suggest that LDLR may play a role in the pathophysiological mechanisms underlying CI/RI.
LDLR is a membrane receptor located on the plasma membrane, capable of binding and internalizing exogenous ligands such as LDL and ApoE. LDLR plays a crucial regulatory role in lipid cholesterol metabolism . Studies have demonstrated that the overexpression of IDOL in cells can inhibit the uptake of LDL by downregulating the protein expression of LDLR, which ultimately leads to hypercholesterolemia. We found that after IDOL knockout, LDLR expression was up-regulated and lipid levels decreased, slowing down the occurrence of CI/RI. Consistent with our research results, there is evidence suggesting that LDLR knockout increases cholesterol levels in brain tissue, thereby promoting neuronal apoptosis . Therefore, the IDOL-LDLR axis provides a promising new treatment approach for the treatment of CI/RI.
In addition, apoptosis, also known as programmed cell death, is intricately associated with CI/RI and differs significantly from cellular necrosis . This process aims to eliminate excess or damaged cells during development, as well as to respond to external stimuli. It serves as a self-regulating mechanism aimed at maintaining the balance of the internal environment within the body. Caspase-3 plays a key role in the executive phase of apoptosis. To further determine whether the IDOL-LDLR axis promotes neuronal apoptosis by up-regulating lipid levels in the mouse brain, we also examined the intracellular expression of Caspase-3 using TUNEL staining. With the upregulation of LDLR expression, there was a significant downregulation in the expression of ApoE and caspase-3. Concurrently, the incidence of apoptosis was markedly reduced. These results suggest that the IDOL-LDLR axis can regulate neuroinflammation and apoptosis by modulating lipid metabolism.. However, the exact role of the IDOL-LDLR axis in regulating the course of CI/RI remains ambiguous, and more research is needed to clarify these relationships.
In summary, our study demonstrates that the IDOL-LDLR axis promotes CI/RI development by modulating lipid levels and identifies a promising therapeutic target for CI/RI.