Oxylipin metabolism is controlled by mitochondrial β-oxidation during bacterial inflammation

Abstract

Oxylipins are potent mediators requiring strict control. How they are removed en masse during infection/inflammation is unknown. Herein, lipopolysaccharide (LPS) dynamically increased their mitochondrial b-oxidation, impacting leukocyte bioactivity. Genetic/pharmacological targeting of CPT1 showed <50 oxylipins were robustly removed by macrophage mitochondria during inflammation in vitro and in vivo. Stable isotope-lipidomics demonstrated secretion-reuptake recycling for 12-HETE and its intermediate metabolites. Oxylipin b-oxidation was uncoupled from oxidative phosphorylation. Transcriptional interrogation of human neonatal sepsis revealed significant upregulation of many candidates, encoding proteins for mitochondrial uptake and b- oxidation of long-chain fatty acyls (ACSL1,3,4, ACADVL, CPT1B, CPT2, HADHB). ACSL1/Acsl1 upregulation was a signature in multiple human/murine macrophage datasets. In summary, mitochondrial b-oxidation is a regulatory metabolic checkpoint for oxylipins during infection. This has implications for patients with CPT1 deficiency, at higher risk of mortality during respiratory infections. We propose that mitochondrial b-oxidation capacity to remove oxylipins during infection may directly influence development of inflammation.

New appreciation for an old pathway: the Lands Cycle moves into new arenas in health and disease

“…This results in sufficient amounts present in cell membranes to have an impact on protein association. In this regard, a role for eoxPL in coagulation has been demonstrated in vitro and in vivo , where the calcium dependent association of factors with PS is significantly enhanced by the presence of HETE-PLs in the membrane itself [ 82 , 83 ]. Here, it is proposed that the electronegative -OH group on the eoxPL push the membrane apart, facilitating interactions of calcium ions with the PS headgroup, and enhancing the ability of coagulation factors to associate with the plasma membrane of platelets or eosinophils.…”

Identification of novel plasma lipid markers of cardiovascular disease risk in White and Black women

“…A list of oxylipids with retention times (RTs) and MRMs is provided as supplement ( STable 4 ). RTs were determined using pure standards purchased from Cayman Chemical and compared to published data (56, 57). RTs were predicted for oxylipids without pure standard using regressions of known standard RTs (STable 4) .…”

Polyunsaturated fatty acids and metabolic health: novel insights

“…Oxylipins may act as both pro- and anti-inflammatory molecules [20,21 ▪ ]. Although oxylipins are triggered in response to inflammatory stimuli, a recent study reported that these same stimuli also programme their removal, for example by upregulation of mitochondrial β-oxidation [22 ▪ ]. In general, an increased presence of ω-3 PUFAs in cell membranes leads to an increased generation of less-inflammatory and pro-resolving mediators as a result of LOX and COX action on ω-3 rather than ω-6 PUFAs [20,23,24].…”

“…DPA is also a substrate for synthesis of SPMs [29]. Recent findings suggest that genetic/pharmacological targeting of carnitine palmitoyl transferase 1, enhances oxylipin removal via mitochondrial β-oxidation independently of oxidative phosphorylation and energy production [22 ▪ ]. Upregulation of many genes is observed in a regulatory metabolic checkpoint for oxylipins during inflammation [22 ▪ ].…”

“…Recent findings suggest that genetic/pharmacological targeting of carnitine palmitoyl transferase 1, enhances oxylipin removal via mitochondrial β-oxidation independently of oxidative phosphorylation and energy production [22 ▪ ]. Upregulation of many genes is observed in a regulatory metabolic checkpoint for oxylipins during inflammation [22 ▪ ]. Thus, lipidomic profiling targeting oxylipins may contribute to deeper understanding the role of these bioactive metabolites in the development and progression of human diseases.…”