BRAIN SOCS3 AND PTP1B-ADIPOSE LEPTIN FEEDBACK AXIS IN ALCOHOLIC HEPATOSTEATOSIS

酒精性肝脂肪变性中的脑 SOCS3 和 PTP1B-脂肪瘦素反馈轴

• 批准号: 8065693
• 负责人: RAJ M LAKSHMAN
• 金额: $ 18.9万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-20 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8065693
• 关键词: 5' -AMP-activated protein kinase; AMP-activated protein kinase kinase; Abbreviations; Acetyl-CoA Carboxylase; Acetylation; Address; Adipose tissue; Affect; Alcoholic Fatty Liver; Alcoholic Liver Diseases; Alcohols; Applications Grants; Back; Binding; Biochemical; Brain; Carnitine O-Palmitoyltransferase; Chemistry; Chronic; Complex; Cytokine Inducible SH2-Containing Protein; Data; Deacetylation; Diet; Down-Regulation; EP300 gene; Enzymes; Ethanol; Experimental Models; Fatty Acids; Fatty acid glycerol esters; Feedback; Genes; Goals; Hepatic; Hypothalamic structure; Knock-out; Lead; Leptin; Leptin resistance; Lipids; Literature; Liver; Malonyl Coenzyme A; Messenger RNA; Molecular Biology; Mus; Neurons; PTPN1 gene; Pathogenesis; Pathology; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Plasma; Plasma Proteins; Process; Protein Tyrosine Phosphatase; Proteins; Regulator Genes; Regulatory Element; Relative (related person); Research; Role; Series; Signal Transduction; Steatohepatitis; Sterols; Up-Regulation; Wild Type Mouse; base; fatty acid oxidation; feeding; histone acetyltransferase; human HDAC1 protein; inhibitor/antagonist; innovation; lipid biosynthesis; mRNA Expression; mouse model; novel; novel therapeutic intervention; oxidation; oxidized lipid; problem drinker; public health relevance; response

DESCRIPTION (provided by applicant): Significance: The proposed research is highly significant because instead of the current dogma that alcoholic hepatosteatosis is exclusively due to liver pathology, our novel hypothesis proposes the following complex interactions of adipose tissue, brain and liver: 1. Alcohol leads to increased expression and secretion of the adipokine, leptin in response to which hypothalamus over-expresses the leptin antagonists, the SOCS3 and PTP1B causing leptin resistance. 2. Alcohol-induced over-expressions of neuronal SOCS3 and PTP1B down regulate hepatic PGC11 and lipid oxidizing genes and up regulate PGC12, SREBP1c and lipogenic genes presumably via the relative decrease in SIRT1 and increase in HAT expressions. 3. Furthermore, the inability of leptin to activate AMPK to P04AMPK preserves the active form of ACC, the key enzyme of lipogenic pathway leading to increased lipogenesis. Simultaneously, the active ACC generates more malonyl CoA, a potent inhibitor of CPT1, the rate limiting enzyme of fatty acid oxidation pathway causing decreased lipid oxidation. Thus, alcohol-induced imbalance in brain-adipose axis feedback is responsible for alcoholic hepatosteatosis. Innovation: This application is innovative because of the following reasons: 1. We may discover that alcoholic liver injury is a complex pathogenic process in which the potential integrated actions of increased leptin from adipose tissue leads to hypothalamic over-expression of SOCS3 and PTP1B that adversely affect hepatic lipid oxidizing and lipogenic genes resulting in steatohepatitis. 2. There is a good potential for identifying a novel role for hypothalamic SOCS3 and/or PTP1B in causing alcoholic liver injury. and 3. We may show a novel way by which aberrations in hypothalamic adipose tissue feed-back axis has an impact on alcoholic liver injury. We provide the following data In support of our novel concepts though not in our mouse models: 1. Alcohol increases plasma leptin. 2. Neuronal SOCS3 KO and PTP1B KO mice do not accumulate liver fat even on a high fat diet. 3. Alcohol up regulates hepatic PGC12 and SREBP1c resulting in increased lipid synthesis. 4. Alcohol down regulates hepatic SIRT1 and PGC11 resulting in decreased lipid oxidation. 5. Alcohol up regulates ACC- and down regulates CPT1-mRNA expressions. 6. Alcohol decreases PO4 AMPK and increases acetylSREBP1c. Specific Aims: Our two aims to address the complex action of alcohol are: Aim 1. Does chronic ethanol up regulate adipose leptin mRNA/protein and plasma leptin with concomitant increase in hypothalamic SOCS3/ PTP1B mRNAs and their corresponding proteins in wild-type mice? Aim 2. Are neuronal SOCS3 KO and/or PTP1B KO mice protected from chronic alcoholic hepatosteatosis? If so, do the underlying mechanisms involve down regulation of PGC12, SREBP1c, and ACC and/or up regulation of SIRT1, PGC11, and CPT1? Reemphasis of Proposal's Innovation: The novelty of this proposal aims to show that alcohol-induced interactions of brain SOCS3/PTP1B-adipose-leptin axis feedback adversely affect hepatic lipid oxidizing and lipogenic genes leading to alcoholic hepatosteatosis. This may lead to novel therapeutic approaches. PUBLIC HEALTH RELEVANCE: We propose to delineate the possible mechanism/s of how the pathogenesis of alcoholic hepatosteatosis involves a complex series of interactions between adipose tissue and brain adversely affect hepatic fat oxidizing and fat synthesizing genes. This may lead to novel therapeutic approaches.

描述（由申请人提供）：意义：所提出的研究是非常重要的，因为我们的新假设提出了脂肪组织、脑和肝脏的以下复杂相互作用，而不是目前的教条，即酒精性脂肪肝完全是由于肝脏病理学造成的：1.酒精导致脂肪因子、瘦素的表达和分泌增加，下丘脑响应于此过表达瘦素拮抗剂、SOCS 3和PTP 1B，引起瘦素抗性。2.酒精诱导的神经元SOCS 3和PTP 1B的过度表达下调肝脏PGC 11和脂质氧化基因，上调PGC 12，SREBP 1c和脂肪生成基因，推测是通过SIRT 1的相对减少和HAT表达的增加。3.此外，瘦素不能将AMPK激活为P04 AMPK，从而保留了ACC的活性形式，ACC是导致脂肪生成增加的脂肪生成途径的关键酶。同时，活性ACC产生更多的丙二酰辅酶A，这是CPT 1的有效抑制剂，CPT 1是脂肪酸氧化途径的限速酶，导致脂质氧化减少。因此，酒精引起的脑脂肪轴反馈失衡是酒精性脂肪肝的原因。创新性：本应用之所以具有创新性，是因为以下原因：1.我们可能会发现，酒精性肝损伤是一个复杂的致病过程，其中脂肪组织中瘦素增加的潜在综合作用导致下丘脑SOCS 3和PTP 1B的过度表达，对肝脏脂质氧化和脂肪生成基因产生不利影响，导致脂肪性肝炎。2.下丘脑SOCS 3和/或PTP 1B在引起酒精性肝损伤中的新作用有很好的潜力。和3.我们可能会显示一个新的方式，通过下丘脑脂肪组织反馈轴的畸变对酒精性肝损伤的影响。 我们提供了以下数据来支持我们的新概念，尽管不是在我们的小鼠模型中：1。酒精增加血浆瘦素。2.神经元SOCS 3 KO和PTP 1B KO小鼠即使在高脂肪饮食下也不积累肝脏脂肪。3.酒精上调肝脏PGC 12和SREBP 1c，导致脂质合成增加。4.酒精下调肝脏SIRT 1和PGC 11，导致脂质氧化减少。5.酒精上调ACC-和下调CPT 1-mRNA的表达。6.酒精降低PO 4 AMPK，增加乙酰SREBP 1c。具体目标：我们的两个目标是解决酒精的复杂作用：目标1。慢性乙醇是否上调野生型小鼠脂肪瘦素mRNA/蛋白和血浆瘦素，同时增加下丘脑SOCS 3/PTP 1B mRNA及其相应蛋白？目标二。神经元SOCS 3 KO和/或PTP 1B KO小鼠是否受到慢性酒精性脂肪肝的保护？如果是这样，潜在的机制是否涉及PGC 12，SREBP 1c和ACC的下调和/或SIRT 1，PGC 11和CPT 1的上调？重新强调提案的创新：该提案的新奇旨在表明酒精诱导的大脑SOCS 3/PTP 1B-脂肪-瘦素轴反馈的相互作用对肝脏脂质氧化和脂肪生成基因产生不利影响，导致酒精性肝脂肪变性。这可能导致新的治疗方法。 公共卫生相关性：我们建议描述酒精性脂肪肝的发病机制涉及脂肪组织和大脑之间的一系列复杂的相互作用如何对肝脏脂肪氧化和脂肪合成基因产生不利影响的可能机制。这可能导致新的治疗方法。