以VLDL为靶点的降脂策略的研究

降脂仍然是动脉粥样硬化性心血管疾病（ASCVD）防治的基石，目前最有效的降脂药物主要以低密度脂蛋白（LDL）为靶点。目前仍缺乏安全有效的以极低密度脂蛋白（VLDL）为靶点的降脂策略。我们前期研究表明TM6SF2蛋白敲除能通过抑制VLDL脂化降低循环中胆固醇和甘油三酯（TG）且不依赖于LDL受体，但伴随肝脏脂质沉积。我们进一步发现TM6SF2相互作用蛋白ACSL5的敲除也能通过调控VLDL进而降低循环中脂质且不伴随肝脏脂质沉积。根据既往研究及我们前期研究结果，我们推测ACSL5蛋白缺失将减少肝脏TG组装入VLDL，产生脂化不完全的VLDL颗粒且该颗粒在循环中能更快的被代谢和清除，进而显著降低血浆TG和胆固醇。申请人拟在LDLR敲除的类人化仓鼠中明确ACSL5敲低的降脂及抗ASCVD的效果，在细胞和动物水平上综合性的研究ACSL5缺陷调控VLDL降脂的机制，为防治ASCVD提供新的思路和靶点。

Lipid-lowering therapy is still the cornerstone of the prevention and treatment of atherosclerotic cardiovascular disease (ASCVD). At present, the most effective lipid-lowering drugs mainly target low-density lipoprotein (LDL). There is still a lack of safe and effective lipid-lowering strategies targeting very low-density lipoprotein (VLDL). Our previous studies have shown that knockout of TM6SF2 can reduce circulating cholesterol and triglycerides (TG) independent of LDL receptors by reducing VLDL lipidation, which also results in liver lipid accumulation. We further found that the knockout of ACSL5, a TM6SF2 interacting protein, can also regulate VLDL to reduce circulating lipids without hepatic lipids accumulation. Based on the results of previous studies and our preliminary data, we hypothesize that the lack of ACSL5 protein will reduce the lipidation of VLDL, resulting in incompletely lipidated VLDL particles. Those particles can be metabolized and cleared faster in circulation, thereby reducing plasma TG and cholesterol. We intend to clarify the lipid-lowering and anti-ASCVD effects of Acsl5 knockdown in Ldlr-knockout humanized hamsters, and comprehensively study the mechanism of lipid-lowering by Acsl5 deficiency via regulating VLDL at the cellular and animal levels, providing new strategies to prevent and treat ASCVD.