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

描述(申请人提供)：意义：拟议的研究具有非常重要的意义，因为与目前认为酒精性肝骨病完全由肝脏病理引起的教条不同，我们的新假说提出了以下脂肪组织、大脑和肝脏的复杂相互作用：1.酒精导致脂肪因子、瘦素和瘦素的表达和分泌增加，从而使下丘脑过度表达瘦素拮抗剂SOCS3和PTP1B，导致瘦素抵抗。2.酒精诱导的神经元SOCS3和PTP1B过度表达下调肝脏PGC11和脂质氧化基因，上调PGC12、SREBP1c和造脂基因，可能是通过相对减少SIRT1和增加HAT表达来实现的。3.此外，瘦素不能激活AMPK到P04AMPK，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，激活的ACC产生更多的丙二酰辅酶A，这是CPT1的有效抑制剂，CPT1是导致脂肪氧化减少的脂肪酸氧化途径的限速酶。因此，酒精引起的脑-脂肪轴反馈失衡是酒精性肝骨病的原因。创新：本应用具有创新性，原因如下：1.酒精性肝损伤是一个复杂的发病过程，脂肪组织中瘦素的潜在综合作用导致下丘脑SOCS3和PTP1B的过度表达，从而对肝脏的脂质氧化和脂肪生成基因产生不利影响，从而导致脂肪性肝炎。2.发现下丘脑SOCS3和/或PTP1B在酒精性肝损伤中可能起到新的作用。3.揭示了下丘脑脂肪组织反馈轴的异常在酒精性肝损伤中的作用机制。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.酒精增加了血浆瘦素。2.神经元SOCS3 KO和PTP1B KO小鼠即使在高脂饮食下也不会积聚肝脏脂肪。3.酒精可上调肝脏PGC12和SREBP1c的表达，导致脂质合成增加。4.酒精可下调肝脏SIRT1和PGC11的表达，从而减少脂质氧化。5.酒精可上调ACC-1和下调CPT1-mRNA的表达。6.酒精降低PO4-AMPK，增加乙酰化SREBP1c。具体目的：我们的两个目的是为了解决酒精的复杂作用：目的1.在野生型小鼠中，慢性酒精是否上调脂肪瘦素mRNA/蛋白和血浆瘦素，并伴随着下丘脑SOCS3/PTP1B mRNAs及其相应蛋白的增加？目的2.神经元SOCS3 KO和/或PTP1B KO小鼠对慢性酒精性肝骨病有保护作用吗？如果是，潜在的机制是否涉及下调PGC12、SREBP1c和ACC和/或上调SIRT1、PGC11和CPT1？再次强调建议的创新：该建议的新颖性旨在表明酒精诱导的脑SOCS3/PTP1B-脂肪-瘦素轴反馈的相互作用对导致酒精性肝骨病的肝脏脂质氧化和脂肪生成基因产生不利影响。这可能会导致新的治疗方法。 公共卫生相关性：我们建议描绘酒精性肝骨病发病机制的可能机制/S，该机制涉及脂肪组织和大脑之间一系列复杂的相互作用，对肝脏脂肪氧化和脂肪合成基因产生不利影响。这可能会导致新的治疗方法。

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.