Inhibition of Δ24-dehydrocholesterol reductase activates pro-resolving lipid mediator biosynthesis and inflammation resolution

Proc Natl Acad Sci U S A. 2019 Oct 8;116(41):20623-20634. doi: 10.1073/pnas.1911992116. Epub 2019 Sep 23.


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 Δ24-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.

Keywords: PUFA; cholesterol; desmosterol; inflammation resolution; lipid mediator.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Arachidonate 12-Lipoxygenase / genetics
  • Arachidonate 12-Lipoxygenase / metabolism
  • Arachidonate 15-Lipoxygenase / genetics
  • Arachidonate 15-Lipoxygenase / metabolism
  • Cholesterol / biosynthesis*
  • Disease Models, Animal
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation*
  • Humans
  • Inflammation Mediators / metabolism*
  • Lipid Metabolism
  • Lipids / analysis*
  • Lipogenesis
  • Liver X Receptors / genetics
  • Liver X Receptors / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Nerve Tissue Proteins / antagonists & inhibitors*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Oxidoreductases Acting on CH-CH Group Donors / antagonists & inhibitors*
  • Oxidoreductases Acting on CH-CH Group Donors / genetics
  • Oxidoreductases Acting on CH-CH Group Donors / metabolism
  • Peritonitis / chemically induced
  • Peritonitis / drug therapy*
  • Peritonitis / metabolism
  • Peritonitis / pathology
  • Phenotype


  • Anti-Inflammatory Agents
  • Inflammation Mediators
  • Lipids
  • Liver X Receptors
  • Nerve Tissue Proteins
  • Cholesterol
  • Arachidonate 12-Lipoxygenase
  • ALOX12 protein, human
  • ALOX15 protein, human
  • Arachidonate 15-Lipoxygenase
  • Oxidoreductases Acting on CH-CH Group Donors
  • DHCR24 protein, human