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

Abstract

Oxylipins are potent biological mediators requiring strict control, but how they are removed en masse during infection and inflammation is unknown. Here we show that lipopolysaccharide (LPS) dynamically enhances oxylipin removal via mitochondrial β-oxidation. Specifically, genetic or pharmacological targeting of carnitine palmitoyl transferase 1 (CPT1), a mitochondrial importer of fatty acids, reveal that many oxylipins are removed by this protein during inflammation in vitro and in vivo. Using stable isotope-tracing lipidomics, we find secretion-reuptake recycling for 12-HETE and its intermediate metabolites. Meanwhile, oxylipin β-oxidation is uncoupled from oxidative phosphorylation, thus not contributing to energy generation. Testing for genetic control checkpoints, transcriptional interrogation of human neonatal sepsis finds upregulation of many genes involved in mitochondrial removal of long-chain fatty acyls, such as ACSL1,3,4, ACADVL, CPT1B, CPT2 and HADHB. Also, ACSL1/Acsl1 upregulation is consistently observed following the treatment of human/murine macrophages with LPS and IFN-γ. Last, dampening oxylipin levels by β-oxidation is suggested to impact on their regulation of leukocyte functions. In summary, we propose mitochondrial β-oxidation as a regulatory metabolic checkpoint for oxylipins during inflammation.

Lipid hydroperoxides and oxylipins are mediators of denervation induced muscle atrophy

“…Lipids were detected in negative ion mode using MRM monitoring with the following parent to daughter ion transitions for lipids that are reported in this study: 12-HETE [M − H] - 319.2/179.1, 15-HETE [M − H] - 319.2/219.1, 13-HODE [M − H] - 295.2/195.1, 15-HETrE [M − H] - 321.2/221.1, 15-HEPE [M − H] - 317.2/219.1, 14-HDOHE [M − H] - 343.2/205.1, 17-HDOHE [M − H] - 343.2/201.1, 13-HOTrE [M − H] - 293.2/195.1. For full details of this scheduled MRM method which detects >100 lipids see: [ 29 ]. We monitored deuterated internal standards using precursor to product ions transitions of 12-HETE- d8 [M − H] - 327.2/184.1, 15-HETE- d8 [M − H] - 327.2/226.1 and 13-HODE- d4 [M − H] - 299.2/198.1.…”

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

“…Oxylipin-containing PL can also be generated by macrophages, although in the case of 15-LOX in humans or 12/15-LOX in mice, this generally involves direct PL oxidation rather than a Lands pathway process [ 76 , 78 , 79 ]. However, supplementation of RAW macrophages with exogenous free HETE, or HETE-esterified to cholesterol can result in a slower rate of HETE-PL formation, via fatty acyl-CoA intermediates, over a period of a few hours [ 80 , 81 ]. A recent study showed that esterification via Lands Pathway can mediate removal of large amounts of 12-HETE by RAW macrophages in vitro [ 81 ].…”

“…However, supplementation of RAW macrophages with exogenous free HETE, or HETE-esterified to cholesterol can result in a slower rate of HETE-PL formation, via fatty acyl-CoA intermediates, over a period of a few hours [ 80 , 81 ]. A recent study showed that esterification via Lands Pathway can mediate removal of large amounts of 12-HETE by RAW macrophages in vitro [ 81 ].…”

Patient Stratification in Sepsis: Using Metabolomics to Detect Clinical Phenotypes, Sub-Phenotypes and Therapeutic Response

“…Lipid mediators play an important role in the acute inflammatory response and resolution of inflammation [ 122 ]. For example, oxylipins are lipid mediators which result from the enzymatic oxidation of poly-unsaturated fatty acids by cytochrome P450s, cyclooxygenases or lipoxygenases during inflammation or infection [ 123 , 124 ]. The oxylipin 14,15-dihydroxyeicosatrienoic acid (DiHETE) ( Figure 1 ) was present in significantly higher concentrations in the serum of patients with septic shock who did not survive compared to survivors, and this oxylipin showed an association with more severe organ dysfunction, especially hepatic failure [ 88 ].…”