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

Evan D. Muse, Shan Yu, Chantle R. Edillor, Jenhan Tao, Nathanael J. Spann, Ty D. Troutman, Jason S. Seidman, Adam Henke, Jason T. Roland, Katherine A. Ozeki, Bonne M. Thompson, Jeffrey G. McDonald, John Bahadorani, Sotirios Tsimikas, Tamar R. Grossman, Matthew S. Tremblay, Christopher K. Glass

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)E4680-E4689
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number20
DOIs
StatePublished - May 15 2018

    Fingerprint

Keywords

  • Cholesterol
  • Hepatocyte
  • LXR
  • Macrophage
  • SREBP

ASJC Scopus subject areas

  • General

Cite this

Muse, E. D., Yu, S., Edillor, C. R., Tao, J., Spann, N. J., Troutman, T. D., Seidman, J. S., Henke, A., Roland, J. T., Ozeki, K. A., Thompson, B. M., McDonald, J. G., Bahadorani, J., Tsimikas, S., Grossman, T. R., Tremblay, M. S., & Glass, C. K. (2018). Cell-specific discrimination of desmosterol and desmosterol mimetics confers selective regulation of LXR and SREBP in macrophages. Proceedings of the National Academy of Sciences of the United States of America, 115(20), E4680-E4689. https://doi.org/10.1073/pnas.1714518115