EUROPEAN SOCIETY FOR BIOMEDICAL RESEARCH ON ALCOHOLISM. 12â15 SEPTEMBER 2015. VALENCIA, SPAIN. SY11-2. ALCOHOL-INDUCED LIVER ...
Alcohol and Alcoholism, 2015, 50(S1) i1–i67
Abstracts
ESBRA 2015 EUROPEAN SOCIETY FOR BIOMEDICAL RESEARCH ON ALCOHOLISM 12–15 SEPTEMBER 2015 VALENCIA, SPAIN
SY11-2 ALCOHOL-INDUCED LIVER INJURY FROM ISOASPARTATE PROTEIN DAMAGE W. G. Carter1, N. A. Osna2, D. J. Tuma2, and K. K. Kharbanda2 1 School of Medicine, University of Nottingham, Royal Derby Hospital Centre, Derby, UK, and 2Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska, USA & Departments of Internal Medicine and Biochemistry, University of Nebraska Medical Center, Omaha, Nebraska, USA The formation of isoaspartate peptide bonds is a major form of protein post-translational damage in vivo. The accumulation of isoaspartate damage is normally restricted by the activity of protein isoaspartyl methyltransferase (PIMT); a methylation enzyme that triggers restoration of a normal peptide bond. Alcohol consumption of 4 week duration inhibited the activity of PIMT and resulted in a significant increase of isoaspartate damage in rat liver cellular proteins. We
hypothesised that PIMT was inhibited by an alcohol-induced increase of hepatocellular S-adenosylhomocysteine (SAH) levels, and this was supported by a demonstration that incubation of hepatocytes with agents that elevate hepatocellular SAH similarly evoked an increase of isoaspartate. Likewise, incubation of hepatocytes with betaine, an agent known to facilitate normalisation of hepatocellular SAH levels, was beneficial for lowering isoaspartate damage. In the absence of therapeutic intervention, isoaspartate levels would be expected to continue to increase from cumulative alcohol consumption with pathological consequences; a process that we have modelled using a mouse knockout of PIMT. We show that the liver proteins that accrue isoaspartate damage after PIMT inhibition due to alcohol consumption mirror those that accumulate isoaspartate in the PIMT knockout. We identified one such liver substrate of PIMT as Carbamoyl phosphate synthase-1 (CPS-1), and also show that CPS-1 protein accumulates in the cytosol in response to alcohol consumption. An alcohol-induced increase of isoaspartate damaged proteins will contribute to liver pathology and may provide a useful bio-monitor of liver injury.
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