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

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 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.

Novel Mechanisms for Resolution of Liver Inflammation: Therapeutic Implications

“…A significant decrease in the phagocytic capacity of macrophages was shown when compared with WT mice, pointing out its central role in directing the conversion of macrophages to a restorative phenotype. 44 Data by Kang and Lee also support the association between LM and macrophage polarization. In an ischemia/reperfusion (IR)-induced sterile liver inflammation model in mice, exogenous resolvin D1 (RvD1) ameliorated hepatic damage.…”

“…These findings correlate with an improved and accelerated resolution phase and support data that link LM and restorative mechanisms following inflammation. 44 Additional evidence of the function carried by MaR1 was seen with the use of 12/15-KO mice which impaired MaR1 synthesis by blocking 12/15-LOX. A significant decrease in the phagocytic capacity of macrophages was shown when compared with WT mice, pointing out its central role in directing the conversion of macrophages to a restorative phenotype.…”

“…The observed upregulation of key enzymatic pathways such as 15-LOX, involved in MaR1 synthesis, also reveals different and new ways in which intracellular lipid metabolism may be manipulated as to achieve and promote resolution. 44…”

Lipid metabolism of leukocytes in the unstimulated and activated states

“…Just recently, Cao et al described a high reproducibility of the platform when analyzing tissue samples [11]. However, while the platform has shown excellent results for reproducibility, relative quantification, and fatty acid compositional analysis [12], it has some limitations. While lipid species are being characterized including fatty acid carbon and double bond number, double bond position and geometry are not defined.…”

“…However, it has become accepted that lipid metabolism is linked to the development of different pathologies as for example diabetes, blood clotting, Alzheimer's disease, and cancer, as well as in physiological processes like the inflammatory response [15,16]. The biosynthesis of red blood cells, monocytes, polymorphonuclear neutrophils (PMNs), and platelets has been shown to be largely dependent on lipids as energy source and modulators of hematopoietic stem and progenitor cell (HSPC) differentiation [12].…”