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，这代表了美国人口的2.5%。 第八大常见死因尽管在这一领域取得了重大进展， 驱动ALD的发作和进展的机制仍不完全清楚。cAMP是第二信使， 通过其效应物（例如蛋白激酶A）在调节多种细胞功能中起关键作用。振幅和 cAMP信号传导的持续时间由磷酸二酯酶（PDE）通过cAMP水解和降解进行微调。 我们的研究表明，乙醇增加了实验性ALD中肝PDE 4的表达， 酒精相关性肝炎（AH）患者的肝脏。然而，其在ALD发病机制中的作用尚不清楚。我们 通过证明Pde 4 b在乙醇中起关键作用，开始阐明PDE 4s在ALD中的作用- 介导的脂肪酸β-氧化损伤和脂肪变性。我们还表明，抑制PDE 4活性， 减轻ALD的体内和体外模型中的肝损伤。然而，乙醇的潜在机制 介导的PDE 4酶诱导尚未确定。此外，PDE 4抑制如何发挥其 对失调的脂质代谢和肝细胞存活的有益作用尚未完全了解。我们 使用ALD的动物和细胞模型的初步研究确定了乙醇和PDE 4的新途径。 介导的调节肝脏脂质代谢和细胞损伤，这是以前从未研究过的。基于 根据我们以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 （CYP 2 E1）介导的缺氧诱导因子1（HIF 1 α）增加诱导肝PDE 4， 导致肝脏脂质代谢失调和损伤。 这些机制研究的具体目标是： 目的1：确定肝细胞中乙醇上调PDE 4的潜在机制。 目的2：确定乙醇/PDE 4介导的从头脂肪生成和肝脏脂肪生成的机制。 脂肪变性 目的3：确定MKP 1在乙醇/PDE 4介导的肝细胞毒性中的作用。 本申请的最终目标是不仅鉴定PDE 4上调的机制，而且鉴定PDE 4上调的机制。 PDE 4在ALD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PDE 4特异性抑制剂的强有力的理由。重要的是，存在有效的PDE 4 已经被FDA批准用于治疗其他炎性疾病过程的抑制剂， 抑制剂可能被重新用于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.