Effects of ethanol on AMP kinase signaling

乙醇对 AMP 激酶信号传导的影响

基本信息

批准号：
7264660
负责人：
DAVID W CRABB
金额：
$ 31.67万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-08-01 至 2009-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7264660
关键词：
1-Butanol 1-Propanol 2,4-Dinitrophenol 5&apos -AMP-activated protein kinase AICA ribonucleotide Acetaldehyde Acetates Acyltransferase Affect Alcoholic Fatty Liver Alcohols Binding Binding Proteins Buffers Calcium Caprylates Carbon Carnitine Cells Charge Coenzyme A Consensus Cultured Cells DNA Binding DUSP1 gene Diet Dinitrophenols Dominant-Negative Mutation Energy-Generating Resources Enzymes Ethanol Fatty Acids Fatty acid glycerol esters Fructose Generations Genes Genetic Transcription Glucose Hepatic Hepatocyte Ionophores Light Lipids Liver Liver diseases MAPK14 gene Metabolic Metabolism Metformin Methylene blue Mitochondria Mus Oligomycins Oxidative Stress PPAR alpha Palmitates Pathogenesis Pathway interactions Peroxisome Proliferator-Activated Receptors Phosphorylation Phosphotransferases Propanols Protein Kinase C Rate Rattus Response Elements Role Route SB 203580 Saturated Fatty Acids Signal Pathway Signal Transduction Sorbitol Source Stearates Sterols Testing Triglycerides Uncoupling Agents Urea adenylate kinase alcohol effect arachidonate beta-Hydroxybutyrate caprylate fatty acid oxidation feeding hepatoma cell inhibitor/antagonist interest kinase inhibitor lipid metabolism liver metabolism long chain fatty acid non-alcoholic fatty liver protein function saturated fat sensor transcription factor

项目摘要

DESCRIPTION (provided by applicant): Control of hepatic lipid metabolism is regulated by the transcription factors sterol response element binding protein (SREBP) and peroxisome proliferator activated receptor (PPAR) alpha. Activation of SREBP induces a battery of enzymes involved in lipid synthesis, including acetyI-CoA carboxylase (ACC). The product of ACC, malonyI-CoA, inhibits fatty acid oxidation by inhibiting carnitine palmitoyl acyltransferase, the enzymatic step required for entry of long chain fatty acids into the mitochondrion. Conversely, PPAR activates a battery of genes encoding enzymes involved in the oxidation of fatty acids. Fatty acid synthesis proceeds when there are excess carbon atoms and energy sources, and fatty acid oxidation occurs when energy is needed. AMP kinase (AMPK) has emerged as an important sensor of the energy state and regulator of intermediary metabolism in liver. AMPK inhibits SREBP and ACC activity. Ethanol treatment of cultured cells and of mice activates SREBP and ACC and reduces the abundance and activity of AMPK. We hypothesize that the effect of ethanol on AMPK is central to its other effects on lipid metabolism. To fully understand this effect of ethanol, which may be of fundamental importance in the pathogenesis of alcoholic fatty liver, we will investigate the mechanisms of inhibition of AMPK by ethanol. There are two broad mechanisms we will study: 1) that ethanol, as a source of carbon and reducing equivalents, inhibits the enzyme via increasing the energy charge of the cell or 2) that ethanol or its metabolites alters signaling pathways that impinge on AMPK, such as oxidative stress signaling and alterations in calcium and PKC activity. We will also examine whether AMPK and PPARa are coordinately regulated by ethanol and if the inhibition of AMPK by ethanol is modulated by the presence of saturated fatty acids. These studies will illuminate this interesting new mechanism for ethanol control of liver metabolism and offers potentials for therapy of alcoholic fatty liver. It may also shed light on the pathogenesis of non-alcoholic fatty liver disease.

描述（由申请人提供）：肝脏脂质代谢的控制由转录因子甾醇反应元件结合蛋白（SREBP）和过氧化物酶体增殖物激活受体（PPAR）α调节。 SREBP 的激活会诱导一系列参与脂质合成的酶，包括乙酰辅酶 A 羧化酶 (ACC)。 ACC 的产物丙二酰辅酶 A 通过抑制肉毒碱棕榈酰酰基转移酶（长链脂肪酸进入线粒体所需的酶促步骤）来抑制脂肪酸氧化。相反，PPAR 激活一系列编码参与脂肪酸氧化的酶的基因。当存在过量的碳原子和能量来源时，脂肪酸合成就会进行，而当需要能量时，就会发生脂肪酸氧化。 AMP 激酶 (AMPK) 已成为肝脏能量状态的重要传感器和中间代谢的调节器。 AMPK 抑制 SREBP 和 ACC 活性。对培养细胞和小鼠进行乙醇处理会激活 SREBP 和 ACC，并降低 AMPK 的丰度和活性。我们假设乙醇对 AMPK 的影响是其对脂质代谢的其他影响的核心。为了充分了解乙醇的这种作用（这可能在酒精性脂肪肝的发病机制中具有根本重要性），我们将研究乙醇抑制 AMPK 的机制。我们将研究两种广泛的机制：1) 乙醇作为碳和还原当量的来源，通过增加细胞的能量电荷来抑制酶，或 2) 乙醇或其代谢物改变影响 AMPK 的信号通路，例如氧化应激信号传导以及钙和 PKC 活性的改变。我们还将检查 AMPK 和 PPARa 是否受乙醇协调调节，以及乙醇对 AMPK 的抑制是否受饱和脂肪酸的存在调节。这些研究将阐明乙醇控制肝脏代谢的这种有趣的新机制，并为治疗酒精性脂肪肝提供潜力。它还可能揭示非酒精性脂肪肝的发病机制。