DHCR24 inhibition upregulates desmosterol without promoting regression of atherosclerotic plaques in APOE*3-Leiden.CETP mice

Abstract

Background and Aims: Inhibition of Delta 24-dehydrocholesterol reductase (DHCR24) leads to accumulation of the cholesterol biosynthesis intermediate desmosterol, which is the endogenous ligand for liver X receptors (LXRs). Activation of LXRs is considered to be atheroprotective as it suppresses inflammation and stimulates cholesterol efflux in macrophages via upregulation of ATP-binding cassette transporters A1 and G1. In the current study we aimed to investigate the effect of the selective DHCR24 inhibitor SH42 on regression of atherosclerotic plaques in APOE*3-Leiden.CETP mice, a well-established model for human-like lipid metabolism. Methods: Mice were fed a Western-type diet (16% fat, 0.15% cholesterol) for 20 weeks to promote plaque development. Subsequently, treatment was started with vehicle or SH42 for 8 weeks while the animals were kept on a regular chow diet. Results: Treatment with SH42 significantly upregulated desmosterol levels in liver and plasma, and led to a small reduction in plasma triglyceride, nonHDL-cholesterol and HDL-cholesterol levels on top of the lipid-lowering effect caused by the dietary switch. While SH42 treatment did not affect immune cell numbers in blood, bone marrow, or spleen, SH42 strongly reduced the number of macrophages found in the peritoneum after thioglycolate injection. Conclusions: While the dietary switch halted atherosclerotic lesion progression, SH42 treatment did not accelerate atherosclerotic lesion regression further.