Phosphodiesterase 4 mediated pathogenic mechanisms in alcohol associated liver disease

磷酸二酯酶 4 介导的酒精相关性肝病的致病机制

• 批准号: 10491252
• 负责人: Leila Gobejishvili
• 金额: $ 35.51万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-22 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10491252
• 关键词: Affect; Alcoholic Liver Diseases; Alcohols; Animal Model; Apoptosis; Attenuated; Automobile Driving; CYP2E1 gene; Cell model; Cell physiology; Cessation of life; Complex; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cytochrome P450; Data; Development; Disease; Enzymes; Ethanol; FDA approved; Fatty Acids; Fatty Liver; Genes; Goals; H19 gene; HIF1A gene; Heavy Drinking; Hepatic; Hepatitis; Hepatocyte; Hydrolysis; Impairment; In Vitro; Inflammatory; Injury; Knockout Mice; Liver; Liver diseases; MAPK phosphatase; MAPK8 gene; Mediating; Metabolic; Mitogen-Activated Protein Kinases; PDE4B; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phosphoric Monoester Hydrolases; Phosphorylation; Play; Population; Process; Regulation; Role; Second Messenger Systems; Signal Transduction; Specificity; Toxic effect; Transcriptional Regulation; United States; Untranslated RNA; Up-Regulation; Work; alcohol effect; base; cell injury; genetic manipulation; hypoxia inducible factor 1; in vitro Model; in vivo; inhibitor; lipid biosynthesis; lipid metabolism; liver injury; member; mortality; new therapeutic target; novel; oxidation; phosphatase-1 kinase; phosphodiesterase IV; phosphoric diester hydrolase; preclinical study; response; transcription factor

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.

2.5％的美国人口受酒精相关肝病（ALD）的影响，该肝病代表 八分之一的死亡率最常见原因。尽管该领域取得了重大进展，但复杂的机制 推动ALD的发作和进展仍未完全理解。营地是第二个播放的使者 通过其作用（例如蛋白激酶A）调节多个细胞功能的关键作用。振幅和 cAMP信号的持续时间由磷酸二酯酶（PDES）通过cAMP水解和降解来微调。 我们的工作表明，乙醇在实验ALD以及在 酒精相关的肝炎（AH）患者的生活。但是，它们在ALD发病机理中的作用尚不清楚。我们 通过证明PDE4B在乙醇中起关键作用，开始阐明PDE4在ALD中的作用 介导的脂肪酸β氧化和脂肪变性的损伤。我们还表明抑制PDE4活性 减弱体内和体外ALD体外模型的肝损伤。但是，乙醇的基本机制 尚未确定介导的PDE4酶的诱导。此外，PDE4抑制如何到期 对失调的脂质代谢和肝细胞生存的有益作用尚不完全了解。我们的 使用ALD的动物和细胞模型的初步研究确定了乙醇和PDE4-的新途径 介导的肝脂质代谢和细胞损伤的调节以前从未进行过检查。基于 关于我们以前的工作和初步数据，我们的中心假设是通过细胞色素P450的乙醇 （CYP2E1）介导的低氧诱导因子1（HIF1α）诱导肝PDE4介导的增加，这 导致肝脂质代谢和损伤的失调。 这些机械研究的具体目标是： 目标1：确定乙醇在肝细胞中的PDE4上调的基本机制。 AIM 2：确定乙醇/PDE4介导的从头脂肪生成和肝的机制 脂肪变性。 AIM 3：确定MKP1在乙醇/PDE4介导的肝细胞中介导的毒性中的作用。 该应用程序的最终目标是不仅确定PDE4上调的机制，还要确定 PDE4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 使用PDE4特异性抑制剂在ALD治疗中使用强的理由。重要的是，有潜在的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 抑制剂可能会重新用于ALD。