Lewandowski Cutler T, Laham Megan S, Thatcher Gregory R J
Department of Pharmaceutical Sciences, University of Illinois College of Pharmacy, Chicago, IL 60612, USA.
Department of Pharmacology and Toxicology, University of Arizona College of Pharmacy, Tucson, AZ 85721, USA.
Acta Pharm Sin B. 2022 Mar;12(3):995-1018. doi: 10.1016/j.apsb.2022.01.011. Epub 2022 Jan 24.
The function of ATP binding cassette protein A1 (ABCA1) is central to cholesterol mobilization. Reduced ABCA1 expression or activity is implicated in Alzheimer's disease (AD) and other disorders. Therapeutic approaches to boost ABCA1 activity have yet to be translated successfully to the clinic. The risk factors for AD development and progression, including comorbid disorders such as type 2 diabetes and cardiovascular disease, highlight the intersection of cholesterol transport and inflammation. Upregulation of ABCA1 can positively impact APOE lipidation, insulin sensitivity, peripheral vascular and blood-brain barrier integrity, and anti-inflammatory signaling. Various strategies towards ABCA1-boosting compounds have been described, with a bias toward nuclear hormone receptor (NHR) agonists. These agonists display beneficial preclinical effects; however, important side effects have limited development. In particular, ligands that bind liver X receptor (LXR), the primary NHR that controls ABCA1 expression, have shown positive effects in AD mouse models; however, lipogenesis and unwanted increases in triglyceride production are often observed. The longstanding approach, focusing on LXR LXR selectivity, is over-simplistic and has failed. Novel approaches such as phenotypic screening may lead to small molecule NHR modulators that elevate ABCA1 function without inducing lipogenesis and are clinically translatable.
ATP结合盒转运蛋白A1（ABCA1）的功能在胆固醇转运中至关重要。ABCA1表达或活性降低与阿尔茨海默病（AD）及其他疾病有关。提高ABCA1活性的治疗方法尚未成功转化应用于临床。AD发生和进展的风险因素，包括2型糖尿病和心血管疾病等合并症，凸显了胆固醇转运与炎症的交叉关联。ABCA1的上调可对载脂蛋白E（APOE）脂化、胰岛素敏感性、外周血管及血脑屏障完整性以及抗炎信号传导产生积极影响。已描述了多种提高ABCA1活性化合物的策略，其中偏向于核激素受体（NHR）激动剂。这些激动剂在临床前研究中显示出有益效果；然而，重要的副作用限制了其开发进程。特别是，与肝脏X受体（LXR）结合的配体，LXR是控制ABCA1表达的主要NHR，在AD小鼠模型中已显示出积极作用；然而，常常观察到脂肪生成增加以及甘油三酯产生的不良变化。长期以来专注于LXR选择性的方法过于简单化且已失败。诸如表型筛选等新方法可能会带来小分子NHR调节剂，其可提高ABCA1功能而不诱导脂肪生成且可实现临床转化。
