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Raw Data for: Lipidome changes indicate oxidative stress, inflammation, and specific loss of phosphatidylserine inflammatory protection in patients with lupus

ABSTRACT: Raw Data for: Lipidome changes indicate oxidative stress, inflammation, and specific loss of phosphatidylserine inflammatory protection in patients with lupus Abstract: Systemic lupus erythematosus (SLE, lupus) is a chronic autoimmune disease which has a complex etiology and suffers from both high false positive rates and false negative rates in diagnosis and classification. Substantial lipid changes have been observed previously in lupus patients, and hence we carried out the most comprehensive lipidomics study in lupus to date using LipidMatch Flow. In this study, we investigated various sub-categories of lupus including lupus nephritis, active versus non-active lupus, as well as comparisons to non-lupus controls. A total of 1,105 unique lipids spanning 36 lipid classes (or sub-classes) were annotated in blood plasma samples; of these, 111 lipids changed significantly between controls and active lupus. We determined for the first-time specific oxidized lipid markers, with oxidized triacylglycerols being the most significantly increased lipid sub-class in active lupus as compared to controls. Other indicators of oxidative stress included decreased lipids containing ether linkages and/or polyunsaturated fatty acids. Increased ceramide (d18:1/16:0) and decreased 20-22 carbons containing species (especially 20:4) indicated an inflammatory response in patients with active lupus. Furthermore, we determined significant downregulation of phosphatidylserines, which are known inflammation suppressors, in patients with lupus and a decrease in Coenzyme Q9 and Q10 with supplementation of lupus patients with these compounds shown to be protective. Several unique lipids with unknown biology are also shown to significantly change in active lupus. Many of these trends were also observed in non-active lupus, suggesting lipidomics related changes may occur early in disease development. In conclusion, this comprehensive lipidomics study expands our knowledge of the lipid alterations associated with lupus, providing insights into disease pathogenesis and depleted lipids which could serve as therapeutic targets.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Dr. John A. Bowden Jeremy Koelmel Diane Kamen

PROVIDER: MSV000099313 | MassIVE |

REPOSITORIES: MassIVE

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Project description:Ferroptosis is a form of regulated cell death driven by lipid peroxidation of polyunsaturated fatty acids (PUFAs). Endogenous PUFAs are nonconjugated PUFAs and their peroxidation proceeds via the hydrogen-atom transfer (HAT) mechanism. We previously reported that lipids with conjugated double bonds undergo lipid peroxidation mostly via a different mechanism, peroxyl radical addition (PRA), and were much more readily oxidizable than nonconjugated ones. In this study, we aim to elucidate the effects of various unsaturated lipids in sensitizing ferroptosis. We found that while some peroxidation-reactive lipids, such as 7-dehydrocholesterol, vitamins D3 and A, and coenzyme Q10, suppress ferroptosis, both nonconjugated and conjugated PUFAs enhanced cell death induced by RSL3, a ferroptosis inducer. Importantly, we showed that conjugated linolenic acid (CLA 18:3) could act as a ferroptosis inducer by itself and conjugated linoleic acid (CLA 18:2) was more potent in sensitizing cells to RSL3-induced cell death than any nonconjugated PUFAs. We next sought to elucidate the mechanism underlying the different ferroptosis-inducing potency of conjugated and nonconjugated PUFAs. Lipidomics revealed that conjugated and nonconjugated PUFAs are incorporated into distinct cellular lipid species. Furthermore, the different peroxidation mechanisms predict the formation of higher levels of reactive electrophilic aldehydes from conjugated PUFAs than nonconjugated PUFAs, which was confirmed by aldehyde-trapping and mass spectrometry. RNA sequencing revealed that protein processing in the endoplasmic reticulum and proteasome are among the most significantly upregulated pathways in cells treated with CLA 18:3, suggesting increased ER stress and activation of unfolded protein response. Significantly, using click chemistry, we observed increased protein adduction by oxidized lipids in cells treated with an alkynylated CLA 18:2 probe. These results suggest that protein damage by lipid electrophiles is a key step in ferroptosis.

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Raw Data for: Lipidome changes indicate oxidative stress, inflammation, and specific loss of phosphatidylserine inflammatory protection in patients with lupus

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