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.
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, 92093-0651, USA.
authors.forename: Nathanael J
authors.initials: NJ
authors.lastname: Spann
authors.forename: Lana X
authors.initials: LX
authors.lastname: Garmire
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: McDonald
authors.forename: David S
authors.initials: DS
authors.lastname: Myers
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Milne
authors.forename: Norihito
authors.initials: N
authors.lastname: Shibata
authors.forename: Donna
authors.initials: D
authors.lastname: Reichart
authors.forename: Jesse N
authors.initials: JN
authors.lastname: Fox
authors.forename: Iftach
authors.initials: I
authors.lastname: Shaked
authors.forename: Daniel
authors.initials: D
authors.lastname: Heudobler
authors.forename: Christian R H
authors.initials: CR
authors.lastname: Raetz
authors.forename: Elaine W
authors.initials: EW
authors.lastname: Wang
authors.forename: Samuel L
authors.initials: SL
authors.lastname: Kelly
authors.forename: M Cameron
authors.initials: MC
authors.lastname: Sullards
authors.forename: Robert C
authors.initials: RC
authors.lastname: Murphy
authors.forename: Alfred H
authors.initials: AH
authors.lastname: Merrill
authors.forename: H Alex
authors.initials: HA
authors.lastname: Brown
authors.forename: Edward A
authors.initials: EA
authors.lastname: Dennis
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Li
authors.forename: Klaus
authors.initials: K
authors.lastname: Ley
authors.forename: Sotirios
authors.initials: S
authors.lastname: Tsimikas
authors.forename: Eoin
authors.initials: E
authors.lastname: Fahy
authors.forename: Shankar
authors.initials: S
authors.lastname: Subramaniam
authors.forename: Oswald
authors.initials: O
authors.lastname: Quehenberger
authors.forename: David W
authors.initials: DW
authors.lastname: Russell
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Glass
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000276:immunology* / Q000378:metabolism; D002784:Cholesterol / Q000031:analogs & derivatives / Q000096:biosynthesis* / Q000378:metabolism; D003897:Desmosterol / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism; D005487:Foam Cells / Q000276:immunology / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D051779:Sterol Regulatory Element Binding Proteins / Q000378:metabolism; D059467:Transcriptome
chemical_list: D005227:Fatty Acids; D011973:Receptors, LDL; D051779:Sterol Regulatory Element Binding Proteins; D003897:Desmosterol; D002784:Cholesterol