Ethanol metabolism generates oxidative stress and chronic ethanol exposure alters mitochondrial function. The central question extant is what events and processes link alcohol-induced mitochondrial dysfunction and ROS generation to local and distal tissue damage. We do not yet know how mitochondria are damaged by ethanol metabolism and ROS formation, the molecular identity(ies) of the toxic materials, nor their specific targets. How ethanol metabolism by the liver leads to damage to surrounding and distal tissue also remains opaque. We also lack reliable circulating markers of the propensity for tissue damage. We recently identified specific oxidatively-fragmented phospholipids that are readily transported into cells, where they intercalate into mitochondrial membranes to initiate mitochondrial-dependent apoptosis. We now find these lipids, the lipid inflammatory mediator Platelet-activating Factor (PAF), and distinctive hydroxylated phospholipids are all increased in the circulation of rats chronically ingesting ethanol. Early results suggest this occurs early in the human syndrome as well. These lipids are therefore circulating markers of endogenous oxidative processes resulting from liver metabolism of ethanol. Moreover, they themselves may induce proximal and distal tissue damage through dysregulation of their selective target, energized mitochondria.
The aims of this application are 1) Define the source, identity, and amounts of circulating lipid oxidation products circulating in animals and human chronically ingesting ethanol. 2) Determine how oxidized lipids affect mitochondrial function, and whether mitochondrial function is compromised in a cell specific fashion. 3) Determine whether PAF acetylhydrolase, an enzyme that specifically hydrolyzes oxidatively-modified phospholipids, protects mitochondrial function of liver cells during ethanol metabolism. Alcoholic liver and tissue damage is a significant public health issue, yet adequate markers of the progression of accruing damage are not available until late in the disease process. This project will validate novel circulating lipids as disease associated markers, but, significantly, because these same lipids induce tissue damage, we will be able to accurately assess future organ damage. ? ? ?

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Special Emphasis Panel (ZAA1-JJ (17))
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Murray, Gary
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Cleveland Clinic Lerner
Other Basic Sciences
Schools of Medicine
United States
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Li, Wei; McIntyre, Thomas M (2015) Platelet-activating factor receptor affects food intake and body weight. Genes Dis 2:255-260
Gupta, Nilaksh; Li, Wei; McIntyre, Thomas M (2015) Deubiquitinases Modulate Platelet Proteome Ubiquitination, Aggregation, and Thrombosis. Arterioscler Thromb Vasc Biol 35:2657-66
Latchoumycandane, Calivarathan; Nagy, Laura E; McIntyre, Thomas M (2015) Myeloperoxidase formation of PAF receptor ligands induces PAF receptor-dependent kidney injury during ethanol consumption. Free Radic Biol Med 86:179-90
Latchoumycandane, Calivarathan; Nagy, Laura E; McIntyre, Thomas M (2014) Chronic ethanol ingestion induces oxidative kidney injury through taurine-inhibitable inflammation. Free Radic Biol Med 69:403-16
Gupta, Nilaksh; Li, Wei; Willard, Belinda et al. (2014) Proteasome proteolysis supports stimulated platelet function and thrombosis. Arterioscler Thromb Vasc Biol 34:160-8
Li, Wei; Gigante, Alba; Perez-Perez, Maria-Jesus et al. (2014) Thymidine phosphorylase participates in platelet signaling and promotes thrombosis. Circ Res 115:997-1006
Srikanthan, S; Li, W; Silverstein, R L et al. (2014) Exosome poly-ubiquitin inhibits platelet activation, downregulates CD36 and inhibits pro-atherothombotic cellular functions. J Thromb Haemost 12:1906-17
Alkhouri, Naim; Berk, Michael; Yerian, Lisa et al. (2014) OxNASH score correlates with histologic features and severity of nonalcoholic fatty liver disease. Dig Dis Sci 59:1617-24
Dadabayev, Alisher R; Yin, Guotian; Latchoumycandane, Calivarathan et al. (2014) Apolipoprotein A1 regulates coenzyme Q10 absorption, mitochondrial function, and infarct size in a mouse model of myocardial infarction. J Nutr 144:1030-6
Stafforini, Diana M; McIntyre, Thomas M (2013) Determination of phospholipase activity of PAF acetylhydrolase. Free Radic Biol Med 59:100-7

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