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

Research output: Contribution to journalArticle

279 Scopus citations

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 languageEnglish (US)
Pages (from-to)138-152
Number of pages15
JournalCell
Volume151
Issue number1
DOIs
StatePublished - Sep 28 2012

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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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