Genomics and Lipidomics of Macrophage Activation

Inflammation and macrophage foam cells are characteristic features of atherosclerotic lesions and obese adipose tissue, but the mechanisms linking lipid accumulation to inflammation are poorly understood. To investigate this relationship, the LIPID MAPS consortium performed global lipidomic and transcriptomic analysis of peritoneal macrophages in wild type and LDL receptor‐deficient mice fed either a normal diet or a high fat/high cholesterol diet. These genetic and dietary interventions dramatically altered the macrophage lipidome and transcriptome, with synergistic effects observed between the high fat diet and LDL receptor deficiency. Unexpectedly, macrophage foam cells recovered from LDL receptor‐deficient mice exhibited a de‐activated, rather than an activated inflammatory phenotype. Several lines of evidence suggest that desmosterol plays a central role in integrating the homeostatic response of peritoneal macrophages to cholesterol accumulation, acting to inhibit SREBP‐target genes that drive cholesterol biosynthesis and simultaneously promoting LXR‐dependent cholesterol efflux and anti‐inflammatory activities. Desmosterol further orchestrates a metabolic adaptation resulting in suppression of most endogenous fatty acid biosynthesis but enhanced production of oleic acid, the primary fatty acid used for cholesterol esterification, and 9Z‐palmitoleic acid, a putative lipokine that exerts insulin‐sensitizing effects in vivo. Together these findings identify integrative functions of desmosterol in the control of cholesterol and fatty acid homeostasis and inflammatory responses in the macrophage.