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Koerner, Andreas; Zhou, Enchen; Muller, Christoph; Mohammed, Yassene; Herceg, Sandra; Bracher, Franz; Rensen, Patrick C. N.; Wang, Yanan; Mirakaj, Valbona; Giera, Martin (2019): Inhibition of Delta 24-dehydrocholesterol reductase activates pro-resolving lipid mediator biosynthesis and inflammation resolution. In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 41: pp. 20623-20634
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Targeting metabolism through bioactive key metabolites is an upcoming future therapeutic strategy. We questioned how modifying intracellular lipid metabolism could be a possible means for alleviating inflammation. Using a recently developed chemical probe (SH42), we inhibited distal cholesterol biosynthesis through selective inhibition of Delta(24)-dehydrocholesterol reductase (DHCR24). Inhibition of DHCR24 led to an antiinflammatory/proresolving phenotype in a murine peritonitis model. Subsequently, we investigated several omics layers in order to link our phenotypic observations with key metabolic alterations. Lipidomic analysis revealed a significant increase in endogenous polyunsaturated fatty acid (PUFA) biosynthesis. These data integrated with gene expression analysis, revealing increased expression of the desaturase Fads6 and the key proresolving enzyme Alox-12/15. Protein array analysis, as well as immune cell phenotype and functional analysis, substantiated these results confirming the antiinflammatory/proresolving phenotype. Ultimately, lipid mediator (LM) analysis revealed the increased production of bioactive lipids, channeling the observed metabolic alterations into a key class of metabolites known for their capacity to change the inflammatory phenotype.