阿托伐他汀通过“LXR-IDOL-LDLR”轴影响胰岛β细胞胆固醇代谢的机制

Hyperlipidemia is a common risk factor for the prevalence of cardiovascular disease (CVD) and diabetes mellitus (DM). However, the paradox is that statins are the first line drugs for treating hyperlipidemia but accumulated evidence also suggests that statins could increase the risk of new-onset type 2 diabetes mellitus (T2DM). In contrast, Familial hypercholesterolemia (FH) patients with mutated the low-density lipoprotein receptor (LDLR) have the low prevalence of T2DM in spite of these people being subjected to long-term statin therapy, suggesting that LDLR and cholesterol metabolism may associate with the prevalence of T2DM. LDLR is up-regulated by The sterol-responsive element binding protein-2 (SREBP2), whereas LDLR is also degraded by (Proprotein convrtase subtilisin/kexin 9) PCSK9 and an E3 ubiquitin ligase as Inducible degrader of the low-density lipoprotein receptor (IDOL). In our preliminary experiment, we found that atorvastatin could up-regulated LDLR in pancreatic islets of mice, which mainly depended on the suppression of IDOL in a pathway that named as LXR-IDOL-LDLR axis. However, the mechanism underlying this axis involving with up-regulation of LDLR is unclear, and the association between this axis and the islet function keeps to be determined. Therefore, we attempt to investigate the mechanism of statins action on LDLR expression in pancreatic islets via the LXR-IDOL-LDLR axis, and to address the etiology of association between statins and T2DM, finally contributing to prevent and treat T2DM.

高血脂是心血管病和糖尿病的共同危险因素，矛盾的是临床上用他汀类药物控制血脂的同时却增加了新发糖尿病风险。相反，低密度脂蛋白受体（LDLR）缺陷的家族性高胆固醇血症病人可对抗这种风险，提示LDLR介导的胆固醇代谢与糖尿病发病密切相关。LDLR的表达主要通过SREBP2来调节，其降解主要通过胞外PCSK9引导LDLR的降解和胞内IDOL介导的E3泛素化来进行。我们前期研证明阿托伐他汀可抑制IDOL并通过其“LXR-IDOL-LDLR”轴来上调小鼠胰岛LDLR的表达。然而，目前不清楚阿托伐他汀通过该轴对胰岛β细胞胆固醇代谢的调控机制，更不清楚该轴是否影响胰岛β细胞功能。因此，我们拟通过转基因动物和细胞实验的方法，研究阿托伐他汀通过“LXR-IDOL-LDLR”轴对胰岛细胞胆固醇的调节机制，阐明他汀类药物引起糖尿病的原因，为降低他汀类药物不良反应，以及探索二型糖尿病新的防治途径提供理论基础。

高血脂是糖尿病重要危险因素，矛盾的是临床上用他汀类药物控制血脂的同时却增加了新发糖尿病风险。相反，人群研究显示低密度脂蛋白受体（LDLR）缺陷可能对抗这种风险，提示LDLR的表达与糖尿病发病密切相关。LDLR的表达主要通过SREBP2来调节，其降解主要通过胞外的PCSK9对LDLR的水解和胞内Idol介导的E3泛素化来进行。我们前期研证明阿托伐他汀能影响小鼠胰岛LDLR的表达并可能通过抑制Idol介导的E3泛素化并通过其“LXR-IDOL-LDLR”轴来实现。然而，目前不清楚阿托伐他汀通过该轴对胰岛B细胞胆固醇代谢的调控机制，更不清楚该轴是否胰岛胰岛B细胞功能。因此，我们拟通过研究阿托伐他汀通过“LXR-IDOL-LDLR”轴对胰岛B细胞胆固醇的调节机制，来阐明阿托伐他汀和别的他汀类药物诱发糖尿病的原因，为降低药物不良反应以及糖尿病的防治提供新的治疗途径。通过本项目的执行，我们发现LDLR是调节胰岛细胞摄入胆固醇的主要途径，过多的胆固醇能够影响胰岛素分泌，他汀类药物可能通过该途径引起糖尿病发生；此外，我们也发现IDOL对胰岛细胞LDLR的调节受血脂及去泛素化酶的影响。