Department of Pharmaceutical Sciences, University of Illinois at Chicago, Chicago, IL, USA.
Department of Medicine, University of Illinois at Chicago, 835 S. Wolcott St., Chicago, IL 60612, USA.
EBioMedicine. 2021 Apr;66:103287. doi: 10.1016/j.ebiom.2021.103287. Epub 2021 Mar 19.
Therapeutic agents with novel mechanisms of action are needed to combat the growing epidemic of type 2 diabetes (T2D) and related metabolic syndromes. Liver X receptor (LXR) agonists possess preclinical efficacy yet produce side effects due to excessive lipogenesis. Anticipating that many beneficial and detrimental effects of LXR agonists are mediated by ABCA1 and SREPB1c expression, respectively, we hypothesized that a phenotypic optimization strategy prioritizing selective ABCA1 induction would identify an efficacious lead compound with an improved side effect profile over existing LXRβ agonists.
We synthesized and characterized a novel small molecule for selective induction of ABCA1 vs. SREBP1c in vitro. This compound was evaluated in both wild-type mice and a high-fat diet (HFD) mouse model of obesity-driven diabetes through functional, biochemical, and metabolomic analysis.
Six weeks of oral administration of our lead compound attenuated weight gain, glucose intolerance, insulin signaling deficits, and adiposity. Global metabolomics revealed suppression of gluconeogenesis, free fatty acids, and pro-inflammatory metabolites. Target identification linked these beneficial effects to selective LXRβ agonism and PPAR/RXR antagonism.
Our observations in the HFD model, combined with the absence of lipogenesis and neutropenia in WT mice, support this novel approach to therapeutic development for T2D and related conditions.
需要具有新型作用机制的治疗剂来对抗 2 型糖尿病（T2D）和相关代谢综合征不断增长的流行。肝 X 受体（LXR）激动剂具有临床前疗效，但由于过度的脂肪生成而产生副作用。预计 LXR 激动剂的许多有益和有害影响分别由 ABCA1 和 SREBP1c 表达介导，我们假设优先选择选择性 ABCA1 诱导的表型优化策略将确定一种有效的先导化合物，与现有 LXRβ 激动剂相比，具有改善的副作用谱。
我们合成并表征了一种新型小分子，用于体外选择性诱导 ABCA1 与 SREBP1c。通过功能、生化和代谢组学分析，该化合物在野生型小鼠和高脂肪饮食（HFD）肥胖型糖尿病小鼠模型中进行了评估。
口服我们的先导化合物 6 周可减轻体重增加、葡萄糖不耐受、胰岛素信号缺陷和肥胖。全局代谢组学揭示了抑制糖异生、游离脂肪酸和促炎代谢物。靶标鉴定将这些有益作用与选择性 LXRβ 激动剂和 PPAR/RXR 拮抗剂联系起来。
我们在 HFD 模型中的观察结果，结合 WT 小鼠中不存在脂肪生成和中性粒细胞减少，支持了这种针对 T2D 和相关疾病的治疗开发的新方法。
