Regulated accumulation of desmosterol integrates macrophage lipid metabolism and inflammatory responses

Nathanael J. Spann; Lana X. Garmire; Jeffrey G. McDonald; David S. Myers; Stephen B. Milne; Norihito Shibata; Donna Reichart; Jesse N. Fox; Iftach Shaked; Daniel Heudobler; Christian R.H. Raetz; Elaine W. Wang; Samuel L. Kelly; M. Cameron Sullards; Robert C. Murphy; Alfred H. Merrill; H. Alex Brown; Edward A. Dennis; Andrew C. Li; Klaus Ley; Sotirios Tsimikas; Eoin Fahy; Shankar Subramaniam; Oswald Quehenberger; David W. Russell; Christopher K. Glass

doi:10.1016/j.cell.2012.06.054

Regulated accumulation of desmosterol integrates macrophage lipid metabolism and inflammatory responses

Nathanael J. Spann, Lana X. Garmire, Jeffrey G. McDonald, David S. Myers, Stephen B. Milne, Norihito Shibata, Donna Reichart, Jesse N. Fox, Iftach Shaked, Daniel Heudobler, Christian R.H. Raetz, Elaine W. Wang, Samuel L. Kelly, M. Cameron Sullards, Robert C. Murphy, Alfred H. Merrill, H. Alex Brown, Edward A. Dennis, Andrew C. Li, Klaus LeySotirios Tsimikas, Eoin Fahy, Shankar Subramaniam, Oswald Quehenberger, David W. Russell, Christopher K. Glass

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Abstract

Inflammation and macrophage foam cells are characteristic features of atherosclerotic lesions, but the mechanisms linking cholesterol accumulation to inflammation and LXR-dependent response pathways are poorly understood. To investigate this relationship, we utilized lipidomic and transcriptomic methods to evaluate the effect of diet and LDL receptor genotype on macrophage foam cell formation within the peritoneal cavities of mice. Foam cell formation was associated with significant changes in hundreds of lipid species and unexpected suppression, rather than activation, of inflammatory gene expression. We provide evidence that regulated accumulation of desmosterol underlies many of the homeostatic responses, including activation of LXR target genes, inhibition of SREBP target genes, selective reprogramming of fatty acid metabolism, and suppression of inflammatory-response genes, observed in macrophage foam cells. These observations suggest that macrophage activation in atherosclerotic lesions results from extrinsic, proinflammatory signals generated within the artery wall that suppress homeostatic and anti-inflammatory functions of desmosterol.

Original language	English
Pages (from-to)	138-152
Number of pages	15
Journal	Cell
Volume	151
Issue number	1
DOIs	https://doi.org/10.1016/j.cell.2012.06.054
State	Published - 28 Sep 2012
Externally published	Yes

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Spann, N. J., Garmire, L. X., McDonald, J. G., Myers, D. S., Milne, S. B., Shibata, N., Reichart, D., Fox, J. N., Shaked, I., Heudobler, D., Raetz, C. R. H., Wang, E. W., Kelly, S. L., Sullards, M. C., Murphy, R. C., Merrill, A. H., Brown, H. A., Dennis, E. A., Li, A. C., ... Glass, C. K. (2012). Regulated accumulation of desmosterol integrates macrophage lipid metabolism and inflammatory responses. Cell, 151(1), 138-152. https://doi.org/10.1016/j.cell.2012.06.054

@article{643174e5f94a4f3791ec32dae2ad068f,

title = "Regulated accumulation of desmosterol integrates macrophage lipid metabolism and inflammatory responses",

abstract = "Inflammation and macrophage foam cells are characteristic features of atherosclerotic lesions, but the mechanisms linking cholesterol accumulation to inflammation and LXR-dependent response pathways are poorly understood. To investigate this relationship, we utilized lipidomic and transcriptomic methods to evaluate the effect of diet and LDL receptor genotype on macrophage foam cell formation within the peritoneal cavities of mice. Foam cell formation was associated with significant changes in hundreds of lipid species and unexpected suppression, rather than activation, of inflammatory gene expression. We provide evidence that regulated accumulation of desmosterol underlies many of the homeostatic responses, including activation of LXR target genes, inhibition of SREBP target genes, selective reprogramming of fatty acid metabolism, and suppression of inflammatory-response genes, observed in macrophage foam cells. These observations suggest that macrophage activation in atherosclerotic lesions results from extrinsic, proinflammatory signals generated within the artery wall that suppress homeostatic and anti-inflammatory functions of desmosterol.",

author = "Spann, {Nathanael J.} and Garmire, {Lana X.} and McDonald, {Jeffrey G.} and Myers, {David S.} and Milne, {Stephen B.} and Norihito Shibata and Donna Reichart and Fox, {Jesse N.} and Iftach Shaked and Daniel Heudobler and Raetz, {Christian R.H.} and Wang, {Elaine W.} and Kelly, {Samuel L.} and Sullards, {M. Cameron} and Murphy, {Robert C.} and Merrill, {Alfred H.} and Brown, {H. Alex} and Dennis, {Edward A.} and Li, {Andrew C.} and Klaus Ley and Sotirios Tsimikas and Eoin Fahy and Shankar Subramaniam and Oswald Quehenberger and Russell, {David W.} and Glass, {Christopher K.}",

year = "2012",

month = sep,

day = "28",

doi = "10.1016/j.cell.2012.06.054",

language = "אנגלית",

volume = "151",

pages = "138--152",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "1",

}

Spann, NJ, Garmire, LX, McDonald, JG, Myers, DS, Milne, SB, Shibata, N, Reichart, D, Fox, JN, Shaked, I, Heudobler, D, Raetz, CRH, Wang, EW, Kelly, SL, Sullards, MC, Murphy, RC, Merrill, AH, Brown, HA, Dennis, EA, Li, AC, Ley, K, Tsimikas, S, Fahy, E, Subramaniam, S, Quehenberger, O, Russell, DW & Glass, CK 2012, 'Regulated accumulation of desmosterol integrates macrophage lipid metabolism and inflammatory responses', Cell, vol. 151, no. 1, pp. 138-152. https://doi.org/10.1016/j.cell.2012.06.054

TY - JOUR

T1 - Regulated accumulation of desmosterol integrates macrophage lipid metabolism and inflammatory responses

AU - Spann, Nathanael J.

AU - Garmire, Lana X.

AU - McDonald, Jeffrey G.

AU - Myers, David S.

AU - Milne, Stephen B.

AU - Shibata, Norihito

AU - Reichart, Donna

AU - Fox, Jesse N.

AU - Shaked, Iftach

AU - Heudobler, Daniel

AU - Raetz, Christian R.H.

AU - Wang, Elaine W.

AU - Kelly, Samuel L.

AU - Sullards, M. Cameron

AU - Murphy, Robert C.

AU - Merrill, Alfred H.

AU - Brown, H. Alex

AU - Dennis, Edward A.

AU - Li, Andrew C.

AU - Ley, Klaus

AU - Tsimikas, Sotirios

AU - Fahy, Eoin

AU - Subramaniam, Shankar

AU - Quehenberger, Oswald

AU - Russell, David W.

AU - Glass, Christopher K.

PY - 2012/9/28

Y1 - 2012/9/28

N2 - Inflammation and macrophage foam cells are characteristic features of atherosclerotic lesions, but the mechanisms linking cholesterol accumulation to inflammation and LXR-dependent response pathways are poorly understood. To investigate this relationship, we utilized lipidomic and transcriptomic methods to evaluate the effect of diet and LDL receptor genotype on macrophage foam cell formation within the peritoneal cavities of mice. Foam cell formation was associated with significant changes in hundreds of lipid species and unexpected suppression, rather than activation, of inflammatory gene expression. We provide evidence that regulated accumulation of desmosterol underlies many of the homeostatic responses, including activation of LXR target genes, inhibition of SREBP target genes, selective reprogramming of fatty acid metabolism, and suppression of inflammatory-response genes, observed in macrophage foam cells. These observations suggest that macrophage activation in atherosclerotic lesions results from extrinsic, proinflammatory signals generated within the artery wall that suppress homeostatic and anti-inflammatory functions of desmosterol.

AB - Inflammation and macrophage foam cells are characteristic features of atherosclerotic lesions, but the mechanisms linking cholesterol accumulation to inflammation and LXR-dependent response pathways are poorly understood. To investigate this relationship, we utilized lipidomic and transcriptomic methods to evaluate the effect of diet and LDL receptor genotype on macrophage foam cell formation within the peritoneal cavities of mice. Foam cell formation was associated with significant changes in hundreds of lipid species and unexpected suppression, rather than activation, of inflammatory gene expression. We provide evidence that regulated accumulation of desmosterol underlies many of the homeostatic responses, including activation of LXR target genes, inhibition of SREBP target genes, selective reprogramming of fatty acid metabolism, and suppression of inflammatory-response genes, observed in macrophage foam cells. These observations suggest that macrophage activation in atherosclerotic lesions results from extrinsic, proinflammatory signals generated within the artery wall that suppress homeostatic and anti-inflammatory functions of desmosterol.

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AN - SCOPUS:84867031028

SN - 0092-8674

VL - 151

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EP - 152

JO - Cell

JF - Cell

IS - 1

ER -

Regulated accumulation of desmosterol integrates macrophage lipid metabolism and inflammatory responses

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