Phosphodiesterase 4 mediated pathogenic mechanisms in alcohol associated liver disease

2.5%的美国人口受到酒精相关性肝病(ALD)的影响，这代表着 第八大最常见的死亡原因。尽管在这一领域取得了重大进展，但复杂的机制 肌萎缩侧索硬化症的发病和发展的原因仍不完全清楚。坎普是第二个扮演的信使 通过其效应器(如蛋白激酶A)调节多种细胞功能的关键作用。幅度和 CAMP信号的持续时间是由磷酸二酯酶(PDE)通过cAMP的水解和降解来微调的。 我们的工作表明，乙醇增加了实验性酒精性肝病患者肝脏PDE4的表达 酒精相关性肝炎(AH)患者的肝脏。然而，它们在ALD发病机制中的作用尚不清楚。我们 通过证明PDE4B在乙醇中起关键作用，开始阐明PDE4S在ALD中的作用。 介导的脂肪酸β氧化和脂肪变性的损害。我们还发现，抑制PDE4的活性 减轻ALD体内和体外模型的肝损伤。然而，乙醇的潜在机制 介导的PDE4酶的诱导还没有确定。此外，PDE4抑制是如何发挥其作用的 对调节失调的脂代谢和肝细胞存活的有益影响尚不完全清楚。我们的 使用ALD动物和细胞模型的初步研究确定了乙醇和PDE4- 调节肝脏脂肪代谢和细胞损伤，这是以前从未被研究过的。基座 根据我们之前的工作和初步数据，我们的中心假设是乙醇通过细胞色素P450 (CYP2E1I)介导的缺氧诱导因子1(HIF1α)的增加诱导肝脏PDE4. 导致肝脏脂质代谢失调和损伤。 这些机械论研究的具体目标是： 目的1：探讨乙醇上调肝细胞PDE4表达的可能机制。 目的2：确定乙醇/PDE4介导的从头脂肪生成和肝脏的机制 脂肪变性。 目的：探讨Mkp1在乙醇/PDE4诱导的肝细胞毒性中的作用。 这项应用的最终目标不仅是确定PDE4上调的机制，还包括 PDE4在ALD发生发展中的作用重要的是，我们预测这些临床前研究将提供 在ALD治疗中使用PDE4特异性抑制剂的充分理由。重要的是，有强大的PDE4 已经被FDA批准用于治疗其他炎症性疾病过程的抑制剂，这些 抑制剂可能会被重新用于ALD。

2.5% of United States population is affected by alcohol-associated liver disease (ALD), which represents the eighth most common cause of mortality. Despite significant progress in the field, the complex mechanisms driving the onset and progression of ALD are still not fully understood. cAMP is a second messenger that plays a critical role in regulating multiple cellular functions via its effectors (e.g. protein kinase A). Amplitude and duration of cAMP signaling is fine-tuned by phosphodiesterases (PDEs) via cAMP hydrolysis and degradation. Our work has shown that ethanol increases expression of hepatic PDE4 in experimental ALD as well as in alcohol-associated hepatitis (AH) patients’ livers. However, their role in ALD pathogenesis is not clear. We started elucidating the role of PDE4s in ALD by demonstrating that Pde4b plays a critical role in ethanol- mediated impairment of fatty acid β-oxidation and steatosis. We also showed that inhibition of PDE4 activity attenuates liver injury in in vivo and in vitro models of ALD. However, underlying mechanisms of ethanol mediated induction of PDE4 enzymes have not been determined. Moreover, how PDE4 inhibition exerts its beneficial effect on dysregulated lipid metabolism and hepatocytes survival is not fully understood. Our preliminary studies using animal and cell models of ALD identified novel pathways of ethanol and PDE4- mediated regulation of hepatic lipid metabolism and cell injury which have never been examined before. Based on our previous work and preliminary data, our central hypothesis is that ethanol via cytochrome p450 (CYP2E1) mediated increase in hypoxia inducible factor 1 (HIF1α) induces hepatic PDE4 which contributes to dysregulation of hepatic lipid metabolism and injury. The specific objectives of these mechanistic studies are to: Aim 1: Determine the underlying mechanisms of PDE4 upregulation by ethanol in hepatocytes. Aim 2: Determine mechanisms underlying ethanol/PDE4-mediated de novo lipogenesis and hepatic steatosis. Aim 3: Determine the role of MKP1 in ethanol/PDE4-mediated toxicity in hepatocytes. The ultimate goal of this application is to identify not only the mechanisms of PDE4 upregulation, but also the role of PDE4s in the development of ALD. Importantly, we predict that these preclinical studies will provide strong rationale using PDE4 specific inhibitors in the treatment of ALD. Importantly, there are potent PDE4 inhibitors that are already FDA-approved for the treatment of other inflammatory disease processes, and these inhibitors could potentially be repurposed for ALD.