Chronic Alcohol Exposure Increases Circulating Bioactive Oxidized Phospholipids

Abstract

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-␣ 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.

To hydrolyze or not to hydrolyze: the dilemma of platelet-activating factor acetylhydrolase

“…2 ) ( 10 ). Such modifi ed phospholipids have been identifi ed in oxidized LDLs (11)(12)(13); in models of oxidative insult such as alcoholic blood ( 14 ), smokers blood ( 15 ), and electronegative LDLs ( 16 ); and in models of cutaneous infl ammation ( 17 ). Notable among these lipids are the oxidatively truncated phospholipids butanoyl/butenoyl PAF/PC ( 11 ), azelaoyl PAF/PC ( 18,19 ), palmitoyl glutaroyl PC, palmitoyl oxovaleryl PC ( 12 ), kodia PC ( 13 ), and many more ( 19 ) ( Table 1 ).…”

Platelet-activating Factor Receptor Agonists Mediate Xeroderma Pigmentosum A Photosensitivity

“…PAF and oxidized glycerophosphocholines (OxGPCs) with PAF activity have been implicated in UVB irradiation-mediated skin inflammation and the systemic immunosuppression known to be a major cause for skin cancers (30 -33). Ox-GPCs have been identified in association with other experimental conditions, including chronic alcohol use or cigarette smoke exposure in rodents (34,35). However, the production of biologically active Ox-GPCs with PAF-R agonistic activity has not been definitively linked to photosensitivity or for that matter shown to cause any other particular disease state.…”

Are we over estimating serum oxidative stress/lipid peroxidation in alcoholic liver diseases? A review

“…Instead, these lipids reflect an unappreciated, temporally distinct, hepatic and non-hepatic response to chronic ethanol exposure. [55] Virgina and co-workers in their rat experiment found that there was no significant change in CAT and vitamin E levels in hepatic tissue of ethanol fed group and control group. [56] Similar results were also found even in non-alcoholic liver disease, Rousselot et al, in their study on non-alcoholic liver disease concluded that routine blood oxidative stress markers probably do not accurately reflect hepatic oxidative stress.…”