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Targeting macrophage liver X receptors by hydrogel‐encapsulated T0901317 reduces atherosclerosis without effect on hepatic lipogenesis
Author(s) -
Ma Chuanrui,
Feng Ke,
Yang Xiaoxiao,
Yang Zhimou,
Wang Zhongyan,
Shang Yuna,
Fan Guanwei,
Liu Lipei,
Yang Shu,
Li Xiaoju,
Han Jihong,
Duan Yajun,
Chen Yuanli
Publication year - 2021
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.15387
Subject(s) - liver x receptor , lipogenesis , endocrinology , medicine , scavenger receptor , steatosis , abca1 , cd36 , nap , foam cell , chemistry , microbiology and biotechnology , biology , cholesterol , receptor , lipoprotein , adipose tissue , nuclear receptor , biochemistry , transcription factor , neuroscience , transporter , gene
Background and Purpose 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. Experimental Approach 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. Key Results 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. Conclusion and Implications 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.