IDOL and dyslipidemia in cardiovascular diseases

摘要 尽管他汀类药物的使用显著减少了主要血管事件，但心血管疾病 心血管疾病(CVD)仍然是主要的死亡原因。应对残余风险的新战略包括 他汀类药物与依折麦布或PCSK9抑制剂联合治疗。最近的临床研究结果表明， 尽管联合疗法在进一步降低低密度脂蛋白方面有效，但其降低的效果并不成比例 心血管事件的发生，可能是由于仍然存在相对较高的血浆甘油三酯。此外，一些患者 无法达到较低的低密度脂蛋白目标水平或对药物不耐受，甘油三酯治疗困难。这些挑战 强调需要新的干预目标和新的治疗方法来治疗血脂异常。离体 在小鼠模型中，Idol被鉴定为针对LDLR、VLDLR和ApoER2的E3泛素连接酶 独立于PCSK9的降解和调节血脂动态平衡。此外，在遗传方面 流行病学研究IDOL与低密度脂蛋白、心血管疾病预后和功能丧失等位基因高度相关 导致极低的低密度脂蛋白和降低心血管疾病的风险。不幸的是，偶像生物学中的内在差异 在老鼠和灵长类动物之间，创造了开发更接近人类的动物模型的需要 偶像生物学，以推动偶像研究进入翻译领域。我们的初步研究表明 兔构成了一个更好的模型来测试Idol作为临床相关靶点的可行性 高脂血症和心血管疾病。事实上，与小鼠不同的是，兔偶像是在肝脏对LXR做出反应而诱导的 激动剂，与猴子和人类相同。偶像基因敲除兔降低低密度脂蛋白和高脂肪 高胆固醇饮食，保持低总胆固醇和低甘油三酯。我们将检验这一假设 通过基因缺陷或小分子抑制剂，降低偶像蛋白的表达水平或活性-将 增加血脂清除，减少高胆固醇血症，高甘油三酯血症和炎症，从而 在减少动脉粥样硬化方面。利用偶像淘汰型、杂合型和野生型兔子，我们将建立偶像 作为目标1中减少动脉粥样硬化的治疗靶点，研究偶像对肝脏介导的作用 血脂清除、饮食诱导的主动脉和冠状动脉粥样硬化及新诺明的影响 开发了小分子偶像抑制剂。在目标2中，我们将深化对偶像KO效应的描述 脂质处理和使用原代兔细胞的生理学我们将定义偶像依赖的机制 肝细胞潜在的脂质清除和体外对新型Idol抑制剂的反应。人类IPSC来源 肝细胞和巨噬细胞与功能获得和丧失相结合将解决 跨物种的机制。通过利用新的偶像兔模型来克服这些目标 目前阻碍《美国偶像》翻译研究的障碍将提供令人信服的证据和新的发现 使Idol翻译研究成为制定有针对性的干预措施的新的可行目标 高脂血症和心血管疾病管理，以进一步减少心血管疾病对全球的整体影响。

ABSTRACT Despite a significant reduction of major vascular events through the use of statins, cardiovascular disease (CVD) continues to be the leading cause of death. New strategies to address the residual risks include combination therapy of statins with ezetimibe or PCSK9 inhibition. Recent clinical findings indicate that, although effective in further reducing LDL-C, combination therapies do not proportionally translate in reduction of CV events, likely from the relatively high plasma triglycerides still present. Furthermore, some patients cannot reach the low LDL-C target levels or are drug intolerant and TG treatment is difficult. These challenges highlight the need for new targets for intervention and novel therapeutic approaches for dyslipidemia. In vitro and in mice models, IDOL was identified as an E3 ubiquitin ligase targeting LDLR, VLDLR and ApoER2 for degradation and regulating plasma lipid homeostasis independently of PCSK9. Furthermore, in genetic epidemiology studies IDOL was highly associated with LDL-C and CVD outcomes and loss-of-function alleles result in extremely low LDL-C and reduced CVD risk. Unfortunately, intrinsic differences in IDOL biology between mice and primates, create the need to develop an animal model that better approximates human IDOL biology in order to advance IDOL research into the translational arena. Our preliminary studies indicate that rabbits constitute a better model to test the feasibility of IDOL as a clinically relevant target for hyperlipidemia and CVD. Indeed, unlike in mice, rabbit IDOL is induced in the liver in response to LXR agonists, same as in monkeys and humans. IDOL knock-out rabbits have decreased LDL-C and upon high fat high cholesterol diet, maintain low total cholesterol and low triglycerides. We will test the hypothesis that reduced IDOL protein expression levels or activity -through gene deficiency or small molecule inhibitors- will increase plasma lipid clearance, reduce hypercholesterolemia, hypertriglyceridemia and inflammation, resulting in reduced atherosclerosis. Using IDOL knock-out, heterozygous and wild type rabbits, we will establish IDOL as a therapeutic target for reducing atherosclerosis in Aim 1, to study IDOL contribution to liver-mediated plasma lipid clearance, diet-induced atherosclerosis in aorta and coronary artery and the effects of newly developed small molecule IDOL inhibitors. In Aim 2, we will deepen the characterization of IDOL KO effects of the physiology of lipid handling and using primary rabbit cells we will define IDOL-dependent mechanisms in hepatocytes underlying lipid clearance and the response in vitro to novel IDOL inhibitors. Human iPSC-derived hepatocytes and macrophages combined with gain- and loss-of-function will address conservation of the mechanisms across species. Completion of these aims by leveraging new IDOL rabbit models to overcome the current barriers to advance IDOL translational research will provide compelling evidences and new findings to enable IDOL translational research as a novel feasible target for development of focused interventions for hyperlipidemia and CVD management in order to further reduce the overall global impact of CVD.