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

描述（由申请人提供）：意义：提出的研究具有高度意义，因为我们的新假设提出了脂肪组织、大脑和肝脏之间的以下复杂相互作用，而不是目前的教条，即酒精性肝骨化症完全由肝脏病理引起。酒精导致脂肪因子和瘦素的表达和分泌增加，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的过表达下调了肝脏PGC11和脂质氧化基因，上调了PGC12、SREBP1c和脂质生成基因，可能是通过SIRT1的相对降低和HAT表达的增加。3. 此外，瘦素无法将AMPK激活为P04AMPK，从而保留了ACC的活性形式，ACC是脂肪生成途径的关键酶，导致脂肪生成增加。同时，活性ACC产生更多的丙二醇辅酶a，这是一种有效的CPT1抑制剂，CPT1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肝骨化病的原因。创新性：本应用具有创新性，原因如下：我们可能会发现，酒精性肝损伤是一个复杂的致病过程，脂肪组织瘦素增加的潜在综合作用导致下丘脑过度表达SOCS3和PTP1B，从而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. 我们很有可能发现下丘脑SOCS3和/或PTP1B在引起酒精性肝损伤中的新作用。和3。我们可能通过下丘脑脂肪组织反馈轴畸变影响酒精性肝损伤的新途径。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：酒精会增加血浆瘦素。2. 神经元SOCS3 KO和PTP1B KO小鼠即使在高脂肪饮食中也不会积累肝脏脂肪。3. 酒精上调肝脏PGC12和SREBP1c，导致脂质合成增加。4. 酒精下调肝脏SIRT1和PGC11，导致脂质氧化降低。5. 酒精上调ACC- mrna表达，下调CPT1-mRNA表达。6. 酒精降低PO4 AMPK，增加乙酰srebp1c。具体目标：我们解决酒精复杂作用的两个目标是：目标1。在野生型小鼠中，慢性乙醇是否上调脂肪瘦素mRNA/蛋白和血浆瘦素，同时增加下丘脑SOCS3/ PTP1B mRNA及其相应蛋白？目标2。神经元SOCS3型KO和/或PTP1B型KO小鼠是否能预防慢性酒精性肝纤维化？如果是这样，潜在的机制是否涉及PGC12、SREBP1c和ACC的下调和/或SIRT1、PGC11和CPT1的上调？再次强调提案的创新：该提案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，导致酒精性肝骨化病。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.