Rationale: Chronic ethanol-induced down regulations of silence regulator gene 1 (SIRT1) and peroxisome proliferator receptor coactivator 1 (PGC1) 1 and up-regulation of PGC12 affect hepatic lipid oxidation and lipogenesis leading to fatty liver and consequent injury. We show that dietary low ?3-fatty acids (?3FA), but not high ?3FA, significantly decreased serum and liver lipids, while Soy Proteins (SP) had similar lipid lowering effects. Therefore, it is clinically relevant to prove that these two novel modulators attenuate alcohol-induced fatty liver and injury potentially by regulating these opposing PGC11 and PGC12 signaling pathway genes. Preliminary Studies: Our rationales are based on our publication records (12 Publications, 1 Review article, 1 book &21 Abstracts in the past 5 years), and on strong preliminary data that are summarized below: Low ?3FA &SP opposed the actions of chronic alcohol by (a) Reducing serum lipids with concomitant decreased fatty liver;(b) Attenuating the up-regulation of hepatic mRNAs of PGC12, SREBP1c and their target lipogenic pathway genes;(c) Preventing the down-regulation of hepatic mRNAs of SIRT1 and PGC11 and their target fatty acid oxidation pathway genes;(d) Preventing the hepatic increase in acetyl-PGC11, its inactive form;(e) Restoring impaired hepatic fatty acid oxidation and gluconeogenesis;And (f) Restoring the hepatic level of PO4AMPK that was decreased by chronic alcohol treatment. (g) By Western blots, we demonstrated concomitant changes in levels of mRNAs of PGC11 and PGC12 signaling pathway genes and the corresponding enzyme proteins caused by chronic alcohol. (h) That PGC11 plays a critical role in alcohol- induced fatty liver was demonstrated by dramatic increase in hepatic lipid score in PGC11-KO mice. (i) PGC12 seems to play a secondary role because PGC12-KO mice still developed alcoholic fatty liver albeit less pronounced than in PGC11-KO mice, presumably because of ethanol-mediated strong inhibition of PGC11.
Specific aims : Based on these rationales and preliminary findings we will address the following specific aims:
Specific Aim 1. Effects of ?3FA and SP 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 ?3FA and SP on Ethanol-induced Up-regulation of Hepatic Lipid Anabolic Transcriptional Coactivators, Lipogenic Genes and de novo Lipid Synthetic Rates.
Specific Aim 3. Mechanisms of Actions of ?3FA &SP on Ethanol-induced Down-regulation of Hepatic Lipid Catabolic Transcriptional Coactivators, Lipid Oxidizing Genes &Fatty Acid Oxidation Rates. Methods of Approach: PI and his team will accomplish these specific aims by using rodents as experimental models with their expertise in molecular biology, immuno- and histo-chemistry and biochemical approaches. PI will also use PGC11-KO and PGC12-KOs mouse models to conclusively prove their specificities in the actions of ethanol, Low 3FA &SP via these signaling pathways in causing/preventing alcoholic fatty liver and injury.
Alcohol-induced down regulations of SIRT1 and PGC11 and up-regulation of PGC12 essentially affect key components of liver physiology leading to Hepatosteatosis. Since low ?3-fatty acids (?3FA) and Soy Protein (SP) are potential modulators of PGC11 via SIRT1 and PGC12, PI proposes that it is therapeutically pertinent to test whether alcoholic Hepatosteatosis can be attenuated by low ?3FA and SP and to elucidate their mechanism/s of action.
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|Varatharajalu, Ravi; Garige, Mamatha; Leckey, Leslie C et al. (2010) Betaine protects chronic alcohol and omega-3 PUFA-mediated down-regulations of PON1 gene, serum PON1 and homocysteine thiolactonase activities with restoration of liver GSH. Alcohol Clin Exp Res 34:424-31|