NOVEL MODULATORS OF ALCOHOL INDUCED METABOLIC AND LIVER INJURY

酒精引起的代谢和肝损伤的新型调节剂

• 批准号: 8307287
• 负责人: RAJ M LAKSHMAN
• 金额: $ 29.93万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8307287
• 关键词: Acetylation; Address; Affect; Alcoholic Fatty Liver; Alcohols; Attenuated; Biochemical; Books; Chemistry; Chronic; Data; Deacetylation; Diet; Down-Regulation; Enzymes; Ethanol; Experimental Models; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Genes; Gluconeogenesis; Goals; Hepatic; Histopathology; Homeostasis; Injury; Lipids; Lipoproteins; Liver; MAP Kinase Gene; MAPK14 gene; Mediating; Messenger RNA; Metabolic; Methods; Molecular Biology; Mus; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Peroxisome Proliferators; Phosphorylation; Physiology; Plasma; Play; Property; Proteins; Publications; Publishing; Records; Regulator Genes; Rodent; Role; Serum; Signal Pathway; Signaling Pathway Gene; Soy Proteins; Specificity; Testing; Time; Transcription Coactivator; Up-Regulation; Western Blotting; abstracting; alcohol abuse therapy; base; clinically relevant; fatty acid oxidation; lipid biosynthesis; mouse model; novel; oxidation; oxidized lipid; prevent; problem drinker; receptor

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：理由：慢性乙醇引起的沉默调节剂基因1（SIRT1）和过氧化物酶体增生剂受体共激活剂1（PGC1）1（PGC1）1（PGC1）的上调影响肝脂质氧化和脂肪生成，从而导致脂肪lipty andty Liver及其脂肪损伤。我们表明，饮食中低的3脂酸（？3FA），但不高的3fa，显着降低了血清和肝脂质，而大豆蛋白（SP）具有相似的脂质降低作用。因此，证明这两个新型调节剂可以通过调节这些相反的PGC11和PGC12信号通路基因来减弱酒精诱导的脂肪肝和损伤是临床上相关的。初步研究：我们的理由是基于我们的出版记录（12个出版物，1个评论文章，1本书和21个摘要中的摘要），以及以下概述的强有力的初步数据：低？3FA和SP反对（A）减少同步脂肪降低的血清脂质的慢性酒精作用。 （b）减轻PGC12，SREBP1C及其靶脂基因途径基因的肝mRNA的上调； （c）防止SIRT1和PGC11的肝mRNA及其靶脂肪酸氧化途径基因的下调； （d）防止乙酰基-PGC11的肝增加，其非活动形式； （e）恢复受损的肝脂肪酸氧化和糖异生； （f）恢复通过慢性酒精治疗降低的PO4AMPK的肝水平。 （g）通过Western印迹，我们证明了PGC11和PGC12信号通路基因的mRNA水平以及由慢性酒精引起的相应酶蛋白的变化。 （h）PGC11在酒精诱导的脂肪肝脏中起着至关重要的作用，这表明了PGC11-KO小鼠肝脂质评分的急剧提高。 （i）PGC12似乎起了次要作用，因为PGC12-KO小鼠仍然患有酒精脂肪肝脏，尽管它比PGC11-KO小鼠的明显不那么明显，这可能是由于乙醇介导的PGC11强抑制了PGC11。具体目的：基于这些理由和初步发现，我们将解决以下具体目的：特定目的1。？3FA和SP对慢性乙醇引起的血浆和肝脂质和脂蛋白的增加，AST，ALT，ALT，ALT，ALT及其与肝组织病理学的相关性。具体目的2。？3FA和SP对乙醇引起的肝脂质合成代谢转录共激活剂，脂肪生成基因和DE NOKE脂质合成率的作用机制。特定目的3。？3FA和SP对乙醇引起的肝脂质分解代谢转录共激活剂的下调，脂质氧化基因和脂肪酸氧化速率的作用机制。方法方法：PI和他的团队将通过将啮齿动物作为实验模型，及其在分子生物学，免疫和组织化学和生化方法方面的专业知识来实现​​这些特定目标。 PI还将使用PGC11-KO和PGC12-KOS小鼠模型来最终证明它们在乙醇，低3FA和SP通过这些信号传导途径引起/预防酒精脂肪肝和损伤的特异性。