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Sci. Signal., 2 October 2012
Vol. 5, Issue 244, p. ec255
[DOI: 10.1126/scisignal.2003657]

EDITORS' CHOICE

Atherosclerosis Macrophages Resist the Effects of Cholesterol Buildup

Ernesto Andrianantoandro

Science Signaling, AAAS, Washington, DC 20005, USA

The accumulation of low-density lipoprotein (LDL, a carrier of cholesterol in the circulation), inflammation, and the transformation of macrophages into foam cells play key roles in the development of atherosclerosis. Cholesterol efflux is stimulated by activation of liver X receptors (LXRs), which are transcription factors activated by oxysterols and which activate genes encoding proteins involved in cholesterol efflux. Desmosterol, an oxysterol produced in the penultimate step of cholesterol biosynthesis, activates LXRs and suppresses proteolytic processing of sterol regulatory element–binding proteins (SREBPs), which are cleaved to form active transcription factors that drive cholesterol biosynthesis. Spann et al. performed lipidomic and transcriptomic analyses of peritoneal macrophages in wild-type or LDL receptor–knockout (LDLR KO) mice fed either a normal-cholesterol, normal-fat (NCNF) diet or a high-cholesterol, high-fat (HCHF) diet. Previous work showed that feeding LDLR KO mice the HCHF diet results in the transformation of macrophages into foam cells. The lipidomic analysis of Spann et al. revealed that desmosterol accumulated in foam cells from LDLR KO mice fed the HCHF diet and was abundant in foam cells from human atherosclerotic lesions. Contrary to expectation, transcripts of Toll-like receptor 4 (TLR4) target genes with annotations linked to inflammation were less abundant in foam cells from LDLR KO mice than in macrophages from wild-type mice, when both mice were fed the HCHF diet. Treatment of primary macrophages from wild-type mice with exogenous desmosterol or with an inhibitor of DHCR24, the enzyme that catalyzes conversion of desmosterol to cholesterol, recapitulated the foam cell transcriptional phenotype of reduced abundance of transcripts of TLR4 target genes. However, primary macrophages from LXRα and -β double-knockout mice failed to exhibit the reduction in abundance of TLR4 target gene transcripts in response to exogenous desmosterol. Thus, the authors propose that desmosterol may limit inflammatory responses by promoting lipid homeostasis in macrophages.

N. J. Spann, L. X. Garmire, J. G. McDonald, D. S. Myers, S. B. Milne, N. Shibata, D. Reichart, J. N. Fox, I. Shaked, D. Heudobler, C. R. H. Raetz, E. W. Wang, S. L. Kelly, M. C. Sullards, R. C. Murphy, A. H. Merrill Jr., H. A. Brown, E. A. Dennis, A. C. Li, K. Ley, S. Tsimikas, E. Fahy, S. Subramaniam, O. Quehenberger, D. W. Russell, C. K. Glass, Regulated accumulation of desmosterol integrates macrophage lipid metabolism and inflammatory responses. Cell 151, 138–152 (2012). [Online Journal]

Citation: E. Andrianantoandro, Macrophages Resist the Effects of Cholesterol Buildup. Sci. Signal. 5, ec255 (2012).



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