Targeting macrophage liver X receptors by hydrogel-encapsulated T0901317 reduces atherosclerosis without effect on hepatic lipogenesis.

Chuanrui Ma, Ke Feng, Xiaoxiao Yang, Zhimou Yang, Zhongyan Wang, Yuna Shang, Guanwei Fan, Lipei Liu, Shu Yang, Xiaoju Li, Jihong Han, Yajun Duan, Yuanli Chen

British journal of pharmacology 2021 Apr

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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. © 2021 The British Pharmacological Society.

Citation

Chuanrui Ma, Ke Feng, Xiaoxiao Yang, Zhimou Yang, Zhongyan Wang, Yuna Shang, Guanwei Fan, Lipei Liu, Shu Yang, Xiaoju Li, Jihong Han, Yajun Duan, Yuanli Chen. Targeting macrophage liver X receptors by hydrogel-encapsulated T0901317 reduces atherosclerosis without effect on hepatic lipogenesis. British journal of pharmacology. 2021 Apr;178(7):1620-1638