Logo Logo
Help
Contact
Switch Language to German
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
Full text not available from 'Open Access LMU'.

Abstract

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.