Regulated Accumulation of Desmosterol Integrates Macrophage Lipid Metabolism and Inflammatory Responses.(Cell 2012,151:138-152)

報告日期: 2013/05/07
報告時間: 15:10/16:00
報告學生: 賴弘岳
講評老師: 蔡曜聲
附件下載: 下載[1313-1365563154-1.pdf] 

Regulated accumulation of desmosterol integrates macrophage lipid metabolism and inflammatory responses

Spann NJ, Garmire LX, McDonald JG, Myers DS, Milne SB, Shibata N, Reichart D, Fox JN, Shaked I, Heudobler D, Raetz CR, Wang EW, Kelly SL, Sullards MC, Murphy RC, Merrill AH Jr, Brown HA, Dennis EA, Li AC, Ley K, Tsimikas S, Fahy E, Subramaniam S, Quehenberger O, Russell DW, Glass CK

Cell. 2012 Sep 28;151(1):138-52

Speaker:賴弘岳                                                         Date2013/05/07  15:10-16:00

Commentator:蔡曜聲老師                                      PlaceRoom 602

Abstract

Macrophage foam cells are characterized by massive accumulation of lipid and contribute to all phases of atherosclerosis, ranging from the initial development of fatty streaks to the rupture of unstable plaques. A relationship also exists between circulating levels of low-density lipoprotein (LDL) cholesterol and inflammatory responses that promote atherosclerosis. Despite these relationships, the mechanisms by which hypercholesterolemia induces the inflammatory response associated with atherosclerotic lesions remain poorly understood. To investigate these relationships, they 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. They provide evidence that regulated accumulation of desmosterol (an intermediate in the cholesterol biosynthetic pathway) 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, and suppresses homeostatic and anti-inflammatory functions of desmosterol. These findings therefore provide impetus for further characterization and development of synthetic desmosterol-like molecules as the basis of new therapeutic interventions in cardiovascular disease.

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