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

Br J Pharmacol. 2021 Apr;178(7):1620-1638. doi: 10.1111/bph.15387. Epub 2021 Feb 23.

Abstract

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.

Keywords: D-Nap-GFFY-T0901317; SR-A; atherosclerosis; fatty liver; macrophages.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atherosclerosis* / drug therapy
  • Atherosclerosis* / metabolism
  • Hydrocarbons, Fluorinated
  • Hydrogels / metabolism
  • Lipogenesis*
  • Liver / metabolism
  • Liver X Receptors / metabolism
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Sulfonamides

Substances

  • Hydrocarbons, Fluorinated
  • Hydrogels
  • Liver X Receptors
  • Sulfonamides
  • T0901317