First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.
Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China.
Br J Pharmacol. 2021 Apr;178(7):1620-1638. doi: 10.1111/bph.15387. Epub 2021 Feb 23.
Targeting macrophage but not hepatocyte liver X receptors (LXRs) can reduce atherosclerosis without effect on hepatic lipogenesis. In this study, we encapsulated LXR ligands with D-Nap-GFFY to form a nanofibre hydrogel (D-Nap-GFFY-T0901317 or GFFY-T0901317) and determined its effect on atherosclerosis, hepatic lipogenesis and the underlying mechanisms involved.
D-Nap-GFFY-T0901317 was subcutaneously injected to proatherogenic diet-fed apoE-deficient (Apoe ) mice, followed by determination of the development of atherosclerosis, liver steatosis and the involved mechanisms, with comparison of T0901317 oral administration.
Subcutaneous injection of D-Nap-GFFY-T0901317 to Apoe mice inhibited atherosclerosis at a comparable level as T0901317 oral administration without effect on hepatic lipogenesis. More importantly, D-Nap-GFFY-T0901317 regressed the advanced lesions. In arterial wall, D-Nap-GFFY-T0901317 reduced macrophage/foam cells, necrotic cores and calcification and increased collagen content. It activated expression of ABCA1/G1 and smooth muscle α-actin, while inhibiting expression of intracellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1). D-Nap-GFFY-T0901317 also reduced serum pro-inflammatory cytokines and facilitated Kupffer cell M2 polarization. Mechanistically, D-Nap-GFFY-T0901317 was selectively taken up by macrophages but not hepatocytes, resulting in activation of macrophage ABCA1/G1 expression, while having no effect on lipogenic genes in hepatocytes. Moreover, the selective uptake of D-Nap-GFFY-T0901317 by macrophages was mainly completed in a scavenger receptor class A-dependent manner.
Our study demonstrates that D-Nap-GFFY-T0901317 reduces atherosclerosis without effect on hepatic lipogenesis by targeting macrophage LXRs selectively, indicating its potential application for atherosclerosis treatment.
靶向巨噬细胞而非肝细胞的肝 X 受体（LXR）可以减少动脉粥样硬化而不影响肝内脂质生成。在这项研究中，我们将 LXR 配体与 D-Nap-GFFY 包裹在一起形成纳米纤维水凝胶（D-Nap-GFFY-T0901317 或 GFFY-T0901317），并确定其对动脉粥样硬化、肝脂肪生成的影响及其潜在机制。
将 D-Nap-GFFY-T0901317 皮下注射到致动脉粥样硬化饮食喂养的载脂蛋白 E 缺陷（Apoe）小鼠中，然后确定动脉粥样硬化、肝脂肪变性的发展及其涉及的机制，并与 T0901317 口服给药进行比较。
D-Nap-GFFY-T0901317 皮下注射到 Apoe 小鼠中，可抑制动脉粥样硬化的发展，其效果与 T0901317 口服给药相当，而对肝内脂质生成无影响。更重要的是，D-Nap-GFFY-T0901317 使晚期病变消退。在动脉壁中，D-Nap-GFFY-T0901317 减少了巨噬细胞/泡沫细胞、坏死核心和钙化，并增加了胶原含量。它激活了 ABCA1/G1 和平滑肌α-肌动蛋白的表达，同时抑制了细胞间黏附分子 1（ICAM-1）和血管细胞黏附分子 1（VCAM-1）的表达。D-Nap-GFFY-T0901317 还降低了血清促炎细胞因子水平，并促进了库普弗细胞 M2 极化。机制上，D-Nap-GFFY-T0901317 被巨噬细胞而非肝细胞选择性摄取，导致巨噬细胞 ABCA1/G1 表达激活，而对肝细胞的脂质生成基因无影响。此外，D-Nap-GFFY-T0901317 被巨噬细胞的选择性摄取主要通过清道夫受体 A 类（scavenger receptor class A，SR-A）依赖性方式完成。
本研究表明，D-Nap-GFFY-T0901317 通过选择性靶向巨噬细胞 LXR 减少动脉粥样硬化而不影响肝内脂质生成，表明其在动脉粥样硬化治疗中的潜在应用。
