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

The beneficial effects of LXR-pathway activation have long been appreciated, but clinical application of synthetic LXR ligands has been limited by coactivation of SREBP1c and consequent hypertriglyceridemia. Natural LXR ligands such as desmosterol do not promote hypertriglyceridemia because of coordinate down-regulation of the SREBP pathway. Here we demonstrate that synthetic desmosterol mimetics activate LXR in macrophages both in vitro and in vivo while suppressing SREBP target genes. Unexpectedly, desmosterol and synthetic desmosterol mimetics have almost no effect on LXR activity in hepatocytes in comparison with conventional synthetic LXR ligands. These findings reveal cell-specific differences in LXR responses to natural and synthetic ligands in macrophages and liver cells that provide a conceptually new basis for future drug development.

Authors:   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
Journal:   Proceedings of the National Academy of Sciences current issue
Volume:   115
edition:   20
Year:   2018
Pages:   E4680
DOI:   10.1073/pnas.1714518115
Publication date:   15-May-2018
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