Control of drug and ethanol metabolism

描述(由申请人提供)：我们已经确定了酒精导致肝脏损害的一种新的潜在机制。具体地说，我们发现乙醇可上调肝脏纤溶酶原激活物抑制物-1(PAI-1)的表达，其表达水平与保护肝脏免受酒精损伤有关。此外，我们还表明，PAI-1-/-小鼠不仅可以预防酒精引起的脂肪肝，而且还可以预防疾病的后期阶段(炎症、坏死和纤维化)。因此，我们假设PAI-1上调在ALD中起因果作用。我们将通过以下具体目标建立在这一假设的基础上。1)PAI-1是否参与小鼠肠内酒精肝损伤？我们将通过研究抑制PAI-1表达对小鼠肠道酒精所致肝损伤的影响来直接检验这一假说。将被测试的具体假设是：a)PAI-1的缺失将保护小鼠免受实验性ALD的伤害，b)PAI-1通过VLDL合成受损而介导酒精后的脂肪变性，c)PAI-1通过纤维蛋白沉积介导慢性酒精暴露期间的肝脏炎症。2.确定酒精诱导PAI-1的作用机制(S)。这一特定目的的目的是确定慢性酒精诱导PAI-1的主要机制。需要检验的具体假设是：a)由于乙醇，TNFa是PAI-1的主要诱导者。2)PAI-1是由酒精诱导的，其机制涉及肝脏胰岛素信号转导受损。3)为了确定PAI-1介导肝纤维化的机制(S)，我们将建立在初步研究的基础上，验证PAI-1也在肝纤维化中起因果作用的假设。将被测试的具体假设是：a)PAI-1-/-小鼠在基质分解水平上受到保护，防止肝纤维化；b)提高PAI-1-/-小鼠的基质分解能力需要基质金属蛋白酶；c)抑制PAI-1将促进已建立的纤维化和肝硬化的恢复。综上所述，我们预计这项工作的结果将确定PAI-1在酒精性肝损伤早期损害(脂肪变性、炎症和坏死)以及疾病后期(即纤维化和肝硬变)水平上的新原因。因此，我们期望这项工作的结果将确定靶向PAI-1作为ALD的一种新的潜在治疗方法。

DESCRIPTION (provided by applicant): We have identified a novel potential mechanism by which alcohol causes liver damage. Specifically, we showed that hepatic expression of plasminogen activator inhibitor-1 (PAI-1) is upregulated by ethanol and the level of expression correlates with protection against liver damage in enteral alcohol model. Furthermore, we showed that PAI-1-/- mice are protected against not only fatty liver due to alcohol, but also later stages of the disease (inflammation, necrosis and fibrosis). We therefore hypothesize that PAI-1 upregulation plays a causal role in ALD. We will build on this hypothesis via the following specific aims. 1) Is PAI-1 involved in enteral alcohol-induced liver injury in mice? We will directly test this hypothesis by investigating the effect of inhibition of PAI-1 expression on liver damage due to alcohol in the enteral mouse model. Specific subhypotheses to be tested are: a) Absence of PAI-1 will protect against experimental ALD in mice, b) PAI-1 mediates steatosis after alcohol via impaired VLDL synthesis, c) PAI-1 mediates hepatic inflammation during chronic alcohol exposure via fibrin deposition. 2. To determine the mechanism(s) by which PAI-1 is induced by alcohol. The purpose of this specific aim is to identify the major mechanisms by which PAI-1 is induced by chronic alcohol. Specific subhypotheses to be tested are: a) TNFa is the major inducer of PAI-1 due to ethanol. b) PAI-1 is induced by alcohol via mechanisms involving impaired hepatic insulin signaling. 3) To determine the mechanism(s) by which PAI-1 mediates hepatic fibrosis we will build on Preliminary Studies testing the hypothesis that PAI-1 also plays a causal role in hepatic fibrosis. Specific subhypotheses to be tested are: a) PAI-1-/- mice are protected against hepatic fibrosis at the level of matrix resolution, b) Matrix metalloproteases are required for enhanced matrix resolution in PAI-1-/- mice, c) Inhibition of PAI-1 will enhance recovery from established fibrosis and cirrhosis. Taken together, we expect the results of this work to identify a new causal role of PAI-1 in alcoholic liver injury at the level of early damage (steatosis, inflammation and necrosis), as well as in later stages of the disease (i.e., fibrosis and cirrhosis). We therefore expect that the results of this work will identify targeting PAI-1 as a new potential therapy for ALD.