The role of hepatocyte cAMP/PDE4 in alcohol-induced liver steatosis and injury

肝细胞cAMP/PDE4在酒精性肝脂肪变性和损伤中的作用

基本信息

  • 批准号:
    8798551
  • 负责人:
  • 金额:
    $ 17.28万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-02-05 至 2017-01-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Alcoholic liver disease (ALD) remains a leading cause of death from liver disease in the United States. Steatosis is the initial, most frequent hepatic manifestation that occurs in response to acute as well as chronic ethanol consumption. Although steatosis is reversible, it is now established that the severity of steatosis predicts the progression of liver disease to more advanced stages including fibrosis and cirrhosis. Alcohol causes hepatic steatosis by enhancing de novo lipogenesis and impairing fatty acid beta-oxidation system with subsequent susceptibility to injury by inflammatory cytokines, particularly TNF. However, gaps remain in our understanding of alcohol-responsive mechanisms that contribute to dysregulation of genes involved in hepatic steatosis and subsequent cytokine hepatotoxicity. Cyclic AMP (cAMP), through activation of protein kinase A (PKA), has been shown to modulate genes involved in lipid metabolism and apoptosis. cAMP levels are tightly regulated through biosynthesis by adenyl cylases (ACs) and hydrolysis by phosphodiesterases (PDEs). Our earlier work shows that expression of cAMP-specific PDE4 is significantly increased in response to alcohol exposure in monocytes/macrophages including hepatic Kupffer cells. Notably, our recent preliminary data suggest that ethanol exposure of primary mouse hepatocytes leads to a significant up-regulation of the PDE4 sub-family of enzymes, PDEA, B and D. Based on these findings we postulate that chronic ethanol feeding decreases cAMP levels in hepatocytes in a PDE4-dependent manner. There is no FDA-approved therapy for any stage of alcoholic liver disease (ALD). The most widely-used (off-label) drug therapies are glucocorticoids and pentoxifylline (PTX). Unfortunately, an important subset of AH patients treated with glucocorticoids have "steroid resistance", and some patients have contraindications to steroid therapy. PTX is a broad spectrum PDE inhibitor with only a weak PDE4 inhibitor activity, and the data available from the limited studies suggest a positive intervention effect. Hence, a more directed intervention aimed at inhibiting PDE4 may be significantly more effective. In this regard our recent preliminary data show that treatment with PDE4 specific inhibitor, rolipram, markedly inhibits hepatic steatosis in ethanol-fed animals. Our central hypothesis is that alcohol exposure increases cAMP degrading PDE4 expression in hepatocytes lowering cAMP levels with a resultant increase in lipogenesis and a decrease in fatty acid beta oxidation, leading to the development of steatosis and sensitization to TNF-induced toxicity. Importantly, as a corollary, lowering PDE4 activity may provide a significant therapeutic approach. The specific objectives of these mechanistic as well as translational studies are 1) to examine the effect of alcohol exposure on hepatocyte PDE4 expression, cAMP metabolism and development of hepatic steatosis and injury and 2) to determine the role of PDE4 subclasses and effect of PDE4 inhibition on the development of alcohol induced hepatic steatosis and injury. Our future goal is to provide a conceptual basis for targeting PDE4 activity as a clinical treatment for alcoholic patients.
描述(由申请人提供):酒精性肝病(ALD)仍然是美国肝病死亡的主要原因。脂肪变性是急性和慢性乙醇消耗引起的最常见的肝脏表现。虽然脂肪变性是可逆的,但现在已经确定脂肪变性的严重程度预测了 肝病进展到更晚期阶段,包括纤维化和肝硬化。酒精通过增强从头脂肪生成和损害脂肪酸β-氧化系统引起肝脂肪变性,随后易受炎性细胞因子(特别是TNF)的损伤。然而,我们对酒精反应机制的理解仍然存在差距,这些机制有助于参与肝脂肪变性和随后的细胞因子肝毒性的基因失调。环磷酸腺苷(cAMP),通过激活蛋白激酶A(PKA),已被证明是调节基因参与脂质代谢和细胞凋亡。cAMP水平通过腺苷酸环化酶(AC)的生物合成和磷酸二酯酶(PDE)的水解来严格调节。我们早期的工作表明,cAMP特异性PDE 4的表达显着增加,在单核细胞/巨噬细胞,包括肝枯否细胞的酒精暴露的响应。值得注意的是,我们最近的初步数据表明,原代小鼠肝细胞的乙醇暴露导致酶PDE 4亚家族PDEA、B和D显著上调。基于这些发现,我们推测慢性乙醇喂养以PDE 4依赖性方式降低肝细胞中的cAMP水平。没有FDA批准的治疗酒精性肝病(ALD)的任何阶段。最广泛使用的(标签外)药物疗法是糖皮质激素和戊茶碱(PTX)。不幸的是,用糖皮质激素治疗的AH患者的一个重要子集具有“类固醇抵抗”,并且一些患者具有类固醇治疗的禁忌症。PTX是一种广谱PDE抑制剂,仅具有较弱的PDE 4抑制剂活性,并且从有限的研究中获得的数据表明具有积极的干预作用。因此,旨在抑制PDE 4的更直接的干预可能更有效。在这方面,我们最近的初步数据表明,治疗与PDE 4特异性抑制剂,咯利普兰,显着抑制乙醇喂养的动物肝脂肪变性。我们的中心假设是,酒精暴露增加了肝细胞中cAMP降解PDE 4的表达,降低了cAMP水平,导致脂肪生成增加和脂肪酸β氧化减少,导致脂肪变性的发展和对TNF诱导的毒性的敏感性。重要的是,作为必然结果,降低PDE 4活性可以提供重要的治疗方法。这些机制和转化研究的具体目的是:1)检查酒精暴露对肝细胞PDE 4表达、cAMP代谢和肝脂肪变性和损伤发展的影响; 2)确定PDE 4亚类的作用和PDE 4抑制对酒精诱导的肝脂肪变性和损伤发展的影响。我们未来的目标是为靶向PDE 4活性作为酒精中毒患者的临床治疗提供概念基础。

项目成果

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Leila Gobejishvili其他文献

Leila Gobejishvili的其他文献

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{{ truncateString('Leila Gobejishvili', 18)}}的其他基金

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:
    10877329
  • 财政年份:
    2021
  • 资助金额:
    $ 17.28万
  • 项目类别:
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
  • 财政年份:
    2021
  • 资助金额:
    $ 17.28万
  • 项目类别:
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:
    10661056
  • 财政年份:
    2021
  • 资助金额:
    $ 17.28万
  • 项目类别:
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:
    10345684
  • 财政年份:
    2021
  • 资助金额:
    $ 17.28万
  • 项目类别:
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:
    10738641
  • 财政年份:
    2021
  • 资助金额:
    $ 17.28万
  • 项目类别:
Pathogenic role of PDE4 in hepatic stellate cell activation and TGF signaling
PDE4 在肝星状细胞活化和 TGF 信号传导中的致病作用
  • 批准号:
    8813881
  • 财政年份:
    2016
  • 资助金额:
    $ 17.28万
  • 项目类别:
The role of hepatocyte cAMP/PDE4 in alcohol-induced liver steatosis and injury
肝细胞cAMP/PDE4在酒精性肝脂肪变性和损伤中的作用
  • 批准号:
    8638593
  • 财政年份:
    2014
  • 资助金额:
    $ 17.28万
  • 项目类别:
Pathogenic role of PDE4 in hepatic stellate cell activation and TGF signaling
PDE4 在肝星状细胞活化和 TGF 信号传导中的致病作用
  • 批准号:
    9904707
  • 财政年份:
  • 资助金额:
    $ 17.28万
  • 项目类别:
Pathogenic role of PDE4 in hepatic stellate cell activation and TGF signaling
PDE4 在肝星状细胞活化和 TGF 信号传导中的致病作用
  • 批准号:
    9293341
  • 财政年份:
  • 资助金额:
    $ 17.28万
  • 项目类别:

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