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Grant Abstract: Novel modulators of Alcohol induced metabolic and liver injury

Grant Number: 5R01AA020720-05
PI Name: Lakshman
Project Title: Novel modulators of Alcohol induced metabolic and liver injury

Abstract: Rationale: Chronic ethanol-induced down regulations of silence regulator gene 1 (SIRT1) and peroxisome proliferator receptor coactivator 1 alpha (PGC1a) and up-regulation of peroxisome proliferator receptor coactivator 1 beta (PGC1ß) affect hepatic lipid oxidation and lipogenesis, leading to fatty liver and ALD. Progress: PI has made significant progress under his ongoing parent R01 grant. Thus, he has established that dietary low ?3-fatty acids (?3FA) and Soy Proteins (SP) significantly decreased serum and liver lipids by restoring chronic alcohol-mediated (i) down regulation of PGC1a and associated lipid oxidation genes and pathway, and (ii) suppressing up regulated PGC1ß and lipid synthetic genes and pathway. The initial work was published in Am. J. Pathol, 2014. Another manuscript on the specific regulatory roles of low ?3-fatty acids and soy proteins on alcoholic hepatosteatosis is being submitted to Am J. Pathology. PI has exciting results using the PGC1a and PGC1ß KO mouse models. PI was the convener and speaker at the 8th International ALPD Meeting held in 2013 in New Delhi and at the 1st World Congress on Liver Disease held in 2014 in Jerusalem. Hypotheses: Spermidine (SN) is a polyamine found many natural foods, which has recently been shown to increase the lifespan of many organisms. Resveratrol (RSV) is a natural polyphenol found in grapes, red wine, berries, etc, that has cardio protective effects. They elicit their actions in an autophagy-dependent fashion through the activation of SIRT1, a NAD+-dependent deacetylase or inactivation of Histone acetyltransferases (HAT). The proposed Administrative Supplement is a logical extension of the above parent grant in which the PI proposes to test the ability and mechanism/s of action of two potentially beneficial dietary supplements in alleviating Alcoholic hepatosteatosis and liver injury. Based on these, PI hypothesizes that both SN and RSV could potentially up-regulate SIRT1/PGC1a and/or down regulate PGC1ß-SREBP1c signaling pathways in alleviating alcoholic hepatosteatosis and liver injury by (i) attenuating the lipogenic pathway and/or (ii) stimulating the lipid oxidizing pathway. Specific Aims: To prove his above hypotheses, PI proposes the following specific aims: Specific Aim 1. Effects of SN and RSV on Chronic Ethanol-induced increases in plasma and hepatic lipids and lipoproteins, AST, ALT and their correlation with liver histopathology. Specific Aim 2. Mechanisms of actions of SN and RSV on Ethanol-induced up-regulation of liver lipid anabolic transcriptional coactivators, lipogenic genes and de novo lipid synthetic rates. Specific Aim 3. Mechanisms of actions of SN and RSV on Ethanol-induced down-regulation of liver lipid catabolic transcriptional coactivators, lipid oxidizing genes and fatty acid oxidation rates. PI plans to accomplish these specific aims using C57BL6 as the mouse model with the application of molecular biology, immuno- and histo-chemistry and biochemical approaches

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