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

15 Citations (Scopus)

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

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Desmosterol
Sterol Regulatory Element Binding Proteins
Macrophages
Hypertriglyceridemia
Cholesterol
Liver X Receptors
Sterol Regulatory Element Binding Protein 1
Foam Cells
Biosynthetic Pathways
Sterols
Protein Binding
Genes
Hepatocytes
Atherosclerosis
Fatty Acids

Keywords

  • Cholesterol
  • Hepatocyte
  • LXR
  • Macrophage
  • SREBP

ASJC Scopus subject areas

  • General

Cite this

Cell-specific discrimination of desmosterol and desmosterol mimetics confers selective regulation of LXR and SREBP in macrophages. / Muse, Evan D.; Yu, Shan; Edillor, Chantle R.; Tao, Jenhan; Spann, Nathanael J.; Troutman, Ty D.; Seidman, Jason S.; Henke, Adam; Roland, Jason T.; Ozeki, Katherine A.; Thompson, Bonne M.; McDonald, Jeffrey G.; Bahadorani, John; Tsimikas, Sotirios; Grossman, Tamar R.; Tremblay, Matthew S.; Glass, Christopher K.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 20, 15.05.2018, p. E4680-E4689.

Research output: Contribution to journalArticle

Muse, ED, Yu, S, Edillor, CR, Tao, J, Spann, NJ, Troutman, TD, Seidman, JS, Henke, A, Roland, JT, Ozeki, KA, Thompson, BM, McDonald, JG, Bahadorani, J, Tsimikas, S, Grossman, TR, Tremblay, MS & Glass, CK 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, vol. 115, no. 20, pp. E4680-E4689. https://doi.org/10.1073/pnas.1714518115
Muse, Evan D. ; Yu, Shan ; Edillor, Chantle R. ; Tao, Jenhan ; Spann, Nathanael J. ; Troutman, Ty D. ; Seidman, Jason S. ; Henke, Adam ; Roland, Jason T. ; Ozeki, Katherine A. ; Thompson, Bonne M. ; McDonald, Jeffrey G. ; Bahadorani, John ; Tsimikas, Sotirios ; Grossman, Tamar R. ; Tremblay, Matthew S. ; Glass, Christopher K. / Cell-specific discrimination of desmosterol and desmosterol mimetics confers selective regulation of LXR and SREBP in macrophages. In: Proceedings of the National Academy of Sciences of the United States of America. 2018 ; Vol. 115, No. 20. pp. E4680-E4689.
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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.",
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AU - Muse, Evan D.

AU - Yu, Shan

AU - Edillor, Chantle R.

AU - Tao, Jenhan

AU - Spann, Nathanael J.

AU - Troutman, Ty D.

AU - Seidman, Jason S.

AU - Henke, Adam

AU - Roland, Jason T.

AU - Ozeki, Katherine A.

AU - Thompson, Bonne M.

AU - McDonald, Jeffrey G.

AU - Bahadorani, John

AU - Tsimikas, Sotirios

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AU - Glass, Christopher K.

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N2 - 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.

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