Regulated accumulation of desmosterol integrates macrophage lipid metabolism and inflammatory responses.

TitleRegulated accumulation of desmosterol integrates macrophage lipid metabolism and inflammatory responses.
Publication TypeJournal Article
Year of Publication2012
AuthorsSpann 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 CM, Murphy RC, Merrill AH, Brown AH, Dennis EA, Li AC, Ley K, Tsimikas S, Fahy E, Subramaniam S, Quehenberger O, Russell DW, Glass CK
JournalCell
Volume151
Issue1
Pagination138-52
Date Published2012 Sep 28
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.

DOI10.1371/journal.pone.0050430
Alternate JournalCell