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Circulating biologically active oxidized phospholipids show on-going and increased oxidative stress in older male mice.

ABSTRACT: The biologically active phospholipids Platelet-activating Factor (PAF) and oxidatively truncated phospholipids from chemical oxidation are increased in the circulation of rats subject to the oxidant stress of chronic ethanol ingestion. Potentially, circulating inflammatory and apoptotic phospholipids correlate to physiologic oxidative stress.PAF and the common oxidatively truncated and biologically active phospholipid azelaoyl phosphatidylcholine (Az-PC) were significantly increased in the plasma of older mice, and in male mice. PAF and Az-PC are very rapidly cleared from the circulation, which was unaffected by age or sex. Platelets exposed to Az-PC display phosphatidylserine on their surface, and occlusive platelet carotid arterial thrombosis is enhanced by aging.Biologically active phospholipids vary in the circulation, with the highest levels being found in older, male mice. Turnover of PAF and the biologically active Az-PC are rapid and are invariant with age and sex, so increased production accounts for the increased concentration and flux of both lipids. Platelets are exposed to plasma Az-PC that depolarizes their mitochondria to increase pro-thrombotic phosphatidylserine expression, and occlusive platelet thrombosis is enhanced in aged mice.Oxidatively modified phospholipids are increased in the circulation during common, mild oxidant stresses of aging, or in male compared to female animals. Turnover of these biologically active phospholipids by rapid transport into liver and kidney is unchanged, so circulating levels reflect continuously increased production.

SUBMITTER: Liu J

PROVIDER: S-EPMC4802831 | biostudies-other | 2013

REPOSITORIES: biostudies-other

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Circulating biologically active oxidized phospholipids show on-going and increased oxidative stress in older male mice.

Liu Jinbo J Li Wei W Chen Rui R McIntyre Thomas M TM

Redox biology 20130130

<h4>Background</h4>The biologically active phospholipids Platelet-activating Factor (PAF) and oxidatively truncated phospholipids from chemical oxidation are increased in the circulation of rats subject to the oxidant stress of chronic ethanol ingestion. Potentially, circulating inflammatory and apoptotic phospholipids correlate to physiologic oxidative stress.<h4>Results</h4>PAF and the common oxidatively truncated and biologically active phospholipid azelaoyl phosphatidylcholine (Az-PC) were s ...[more]

PMID: 25499575

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Project description:Ethanol metabolism by liver generates short lived reactive oxygen species that damage liver but also affects distal organs through unknown mechanisms. We hypothesized that dissemination of liver oxidative stress proceeds through release of biologically active oxidized lipids to the circulation. We searched for these by tandem mass spectrometry in plasma of rats fed a Lieber-DeCarli ethanol diet or in patients with established alcoholic liver inflammation, steatohepatitis. We found a severalfold increase in plasma peroxidized phosphatidylcholines, inflammatory and pro-apoptotic oxidatively truncated phospholipids, and platelet-activating factor, a remarkably potent and pleiotropic inflammatory mediator, in rats chronically ingesting ethanol. Circulating peroxidized phospholipids also increased in humans with established steatohepatitis. However, reactive oxygen species generated by liver ethanol catabolism were not directly responsible for circulating oxidized phospholipids because the delayed appearance of these lipids did not correlate with ethanol exposure, hepatic oxidative insult, nor plasma alanine transaminase marking hepatocyte damage. Rather, circulating oxidized lipids correlated with steatohepatitis and tumor necrosis factor-alpha deposition in liver. The organic osmolyte 2-aminoethylsulfonic acid (taurine), which reduces liver endoplasmic reticulum stress and inflammation, even though it is not an antioxidant, abolished liver damage and the increase in circulating oxidized phospholipids. Thus, circulating oxidized phospholipids are markers of developing steatohepatitis temporally distinct from oxidant stress associated with hepatic ethanol catabolism. Previously, circulating markers of the critical transition to pathologic steatohepatitis were unknown. Circulating oxidatively truncated phospholipids are pro-inflammatory and pro-apoptotic mediators with the potential to systemically distribute the effect of chronic ethanol exposure. Suppressing hepatic inflammation, not ethanol catabolism, reduces circulating inflammatory and apoptotic agonists.

Project description:ObjectivesAssess the prevalence of hypogonadism in older male Veterans by comparing direct measurements of total testosterone (T) and bioavailable testosterone (BioT) versus indirect BioT values derived from existing and newly developed regression analyses.DesignCohort study.SettingMalcom Randall VA Medical Center, Gainesville, FL.ParticipantsCommunity-dwelling male Veterans aged 60 and older (n = 203).MeasurementsTotal T, BioT, albumin, sex hormone-binding globulin (SHBG), and body mass index were evaluated. Blood values were assessed via liquid chromatography-tandem mass spectrometry (LC-MS/MS) and clinical or commercially available immunoassays to compare accuracy among assessment techniques. Existing and newly developed multiple regression analyses were evaluated to assess accuracy in predicting BioT.ResultsTotal T was 13.80 ± 6.25 nmol/L (398 ± 180 ng/dL) and was low (≤10.4 nmol/L or ≤300 ng/dL) in 34% of participants. SHBG was 58 ± 35 nmol/L and elevated (≥62 nmol/L) in 36% of participants. BioT was 1.94 ± 0.97 nmol/L (56 ± 28 ng/dL), with 72% of participants below the clinical cutoff (≤2.43 nmol/L or ≤70 ng/dL). Albumin was within the normal clinical range. Total T and BioT measured via immunoassay and LC-MS/MS were moderately to highly correlated, with no differences between assessment methods. Several existing predictive equations overestimated BioT by 74% to 166% within our cohort (P < .001). A newly developed regression model that included total T, SHBG, albumin, and age more accurately predicted BioT, with values correlated (r = 0.508, P < .001) and comparable to LC-MS/MS.ConclusionIn our cohort, the prevalence of low total T was higher and low BioT was markedly higher than reported in the general age-matched population, indicating a greater incidence of hypogonadism in older male Veterans. In addition, existing empiric formulae, derived from other populations produced BioT values that were considerably greater than those directly measured, whereas our newly developed regression analysis provides improved predictive capabilities for older male Veterans.

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Circulating biologically active oxidized phospholipids show on-going and increased oxidative stress in older male mice.

Publications

Circulating biologically active oxidized phospholipids show on-going and increased oxidative stress in older male mice.

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