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Proc Natl Acad Sci U S A. 2018 May 15;115(20):E4680-E4689. doi: 10.1073/pnas.1714518115. Epub 2018 Apr 9.

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

Author information

1
Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093.
2
Division of Cardiovascular Diseases, Scripps Clinic, Scripps Translational Science Institute, La Jolla, CA 92037.
3
California Institute for Biomedical Research, La Jolla, CA 92037.
4
Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX 75390.
5
Department of Medicine, University of California, San Diego, La Jolla, CA 92093.
6
Ionis Pharmaceuticals, Carlsbad, CA 92010.
7
Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093; ckg@ucsd.edu.

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.

KEYWORDS:

LXR; SREBP; cholesterol; hepatocyte; macrophage

PMID:
29632203
PMCID:
PMC5960280
DOI:
10.1073/pnas.1714518115
[Indexed for MEDLINE]
Free PMC Article

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