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Administration of an LXR agonist promotes atherosclerotic lesion remodelling in murine inflammatory arthritis

Objectives: The leading cause of mortality in patients with rheumatoid arthritis is atherosclerotic cardiovascular disease (CVD). We have shown that murine arthritis impairs atherosclerotic lesion regression, because of cellular cholesterol efflux defects in haematopoietic stem and progenitor cells (HSPCs), causing monocytosis and impaired atherosclerotic regression. Therefore, we hypothesised that improving cholesterol efflux using a Liver X Receptor (LXR) agonist would improve cholesterol efflux and improve atherosclerotic lesion regression in arthritis.

Methods: Ldlr -/- mice were fed a western-type diet for 14 weeks to initiate atherogenesis, then switched to a chow diet to induce lesion regression and divided into three groups; (1) control, (2) K/BxN serum transfer inflammatory arthritis (K/BxN) or (3) K/BxN arthritis and LXR agonist T0901317 daily for 2 weeks.

Results: LXR activation during murine inflammatory arthritis completely restored atherosclerotic lesion regression in arthritic mice, evidenced by reduced lesion size, macrophage abundance and lipid content. Mechanistically, serum from arthritic mice promoted foam cell formation, demonstrated by increased cellular lipid accumulation in macrophages and paralleled by a reduction in mRNA of the cholesterol efflux transporters Abca1, Abcg1 and Apoe. T0901317 reduced lipid loading and increased Abca1 and Abcg1 expression in macrophages exposed to arthritic serum and increased ABCA1 levels in atherosclerotic lesions of arthritic mice. Moreover, arthritic clinical score was also attenuated with T0901317.

Conclusion: Taken together, we show that the LXR agonist T0901317 rescues impaired atherosclerotic lesion regression in murine arthritis because of enhanced cholesterol efflux transporter expression and reduced foam cell development in atherosclerotic lesions.

Comments：

The study aimed to investigate whether improving cholesterol efflux using a Liver X Receptor (LXR) agonist could improve atherosclerotic lesion regression in arthritis. Ldlr-/- mice were fed a western-type diet to initiate atherogenesis, then switched to a chow diet to induce lesion regression and divided into three groups: control, K/BxN serum transfer inflammatory arthritis (K/BxN), or K/BxN arthritis and LXR agonist T0901317 daily for 2 weeks.

The results showed that LXR activation during murine inflammatory arthritis completely restored atherosclerotic lesion regression in arthritic mice, evidenced by reduced lesion size, macrophage abundance, and lipid content. The serum from arthritic mice promoted foam cell formation, as shown by increased cellular lipid accumulation in macrophages, paralleled by a reduction in mRNA of the cholesterol efflux transporters Abca1, Abcg1, and Apoe. T0901317 reduced lipid loading and increased Abca1 and Abcg1 expression in macrophages exposed to arthritic serum, and increased ABCA1 levels in atherosclerotic lesions of arthritic mice. Moreover, arthritic clinical score was also attenuated with T0901317.

In conclusion, the study demonstrates that the LXR agonist T0901317 rescues impaired atherosclerotic lesion regression in murine arthritis by enhancing cholesterol efflux transporter expression and reducing foam cell development in atherosclerotic lesions. These findings suggest that LXR agonists may have potential therapeutic benefits for patients with rheumatoid arthritis and atherosclerotic cardiovascular disease.

Related Products

Cat.No. Product Name Information
S7076 T0901317 T0901317 is a potent and selective agonist for both LXR and FXR, with EC50 of 20nM for LXRα and 5 μM for FXR, respectively. T0901317 is a dual inverse agonist of RORα and RORγ with Ki of 132 nM and 51 nM, respectively. T0901317 significantly suppresses cell proliferation and induces apoptosis.

Related Targets

ROR FXR Liver X Receptor Apoptosis related