Cell-specific discrimination of desmosterol and desmosterol mimetics confers selective regulation of LXR and SREBP in macrophages

ED Muse, S Yu, CR Edillor, J Tao… - Proceedings of the …, 2018 - National Acad Sciences
ED Muse, S Yu, CR Edillor, J Tao, NJ Spann, TD Troutman, JS Seidman, A Henke
Proceedings of the National Academy of Sciences, 2018National Acad Sciences
Activation of liver X receptors (LXRs) with synthetic agonists promotes reverse cholesterol
transport and protects against atherosclerosis in mouse models. Most synthetic LXR
agonists also cause marked hypertriglyceridemia by inducing the expression of sterol
regulatory element-binding protein (SREBP) 1c and downstream genes that drive fatty acid
biosynthesis. Recent studies demonstrated that desmosterol, an intermediate in the
cholesterol biosynthetic pathway that suppresses SREBP processing by binding to SCAP …
Activation of liver X receptors (LXRs) with synthetic agonists promotes reverse cholesterol transport and protects against atherosclerosis in mouse models. Most synthetic LXR agonists also cause marked hypertriglyceridemia by inducing the expression of sterol regulatory element-binding protein (SREBP)1c and downstream genes that drive fatty acid biosynthesis. Recent studies demonstrated that desmosterol, an intermediate in the cholesterol biosynthetic pathway that suppresses SREBP processing by binding to SCAP, also binds and activates LXRs and is the most abundant LXR ligand in macrophage foam cells. Here we explore the potential of increasing endogenous desmosterol production or mimicking its activity as a means of inducing LXR activity while simultaneously suppressing SREBP1c-induced hypertriglyceridemia. Unexpectedly, while desmosterol strongly activated LXR target genes and suppressed SREBP pathways in mouse and human macrophages, it had almost no activity in mouse or human hepatocytes in vitro. We further demonstrate that sterol-based selective modulators of LXRs have biochemical and transcriptional properties predicted of desmosterol mimetics and selectively regulate LXR function in macrophages in vitro and in vivo. These studies thereby reveal cell-specific discrimination of endogenous and synthetic regulators of LXRs and SREBPs, providing a molecular basis for dissociation of LXR functions in macrophages from those in the liver that lead to hypertriglyceridemia.
National Acad Sciences