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: 8798551
• 负责人: Leila Gobejishvili
• 金额: $ 17.28万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/8798551
• 关键词: ADD-1 protein; Acute; Adenylate Cyclase; Affect; Alcoholic Liver Diseases; Alcohols; Anabolism; Animal Feed; Apoptosis; Apoptotic; Cause of Death; Cell physiology; Cessation of life; Chronic; Cirrhosis; Clinical Treatment; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclic AMP-Responsive DNA-Binding Protein; Data; Development; Endotoxins; Enzymes; Ethanol; FDA approved; Family; Fatty Acids; Fatty Liver; Fibrosis; Future; Genes; Glucocorticoids; Goals; Health; Hepatic; Hepatocyte; Hepatorenal Syndrome; Hepatotoxicity; Homeostasis; Hydrolysis; In Vitro; Individual; Inflammatory; Injury; Injury to Liver; Intervention; Knock-out; Kupffer Cells; Label; Liver; Liver diseases; Metabolism; Mus; Patients; Pentoxifylline; Peroxisome Proliferator-Activated Receptors; Pharmacotherapy; Phosphodiesterase Inhibitors; Phosphorylation; Play; Predisposition; Prevention; Regulation; Role; Rolipram; Second Messenger Systems; Severities; Staging; Steroid Resistance; Steroid therapy; Stimulus; System; TNF gene; Therapeutic; Toxic effect; United States; Up-Regulation; Work; alcohol effect; alcohol exposure; alcohol response; base; chronic alcohol ingestion; cytokine; fatty acid oxidation; feeding; in vivo; inhibitor/antagonist; intervention effect; lipid biosynthesis; lipid metabolism; liver injury; macrophage; monocyte; mortality; oxidation; phosphoric diester hydrolase; problem drinker; receptor; response; second messenger; translational study

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。脂肪变性是响应急性和慢性乙醇消耗而发生的最初，最常见的肝表现。尽管脂肪变性是可逆的，但现在已经确定脂肪变性的严重程度可以预测 肝病的进展到更晚期的阶段，包括纤维化和肝硬化。酒精通过增强从头脂肪生成并损害脂肪酸β-氧化系统，随后因炎症细胞因子（尤其是TNF）损伤而造成肝脏脂肪变性。然而，我们对酒精反应性机制的理解仍然存在，这些机制导致肝脂肪变性和随后的细胞因子肝毒性的基因失调。通过激活蛋白激酶A（PKA）的激活，环状AMP（CAMP）已被证明可以调节参与脂质代谢和凋亡的基因。 cAMP水平通过腺基二酶（AC）和磷酸二酯酶水解（PDES）的生物合成严格调节。我们的较早工作表明，cAMP特异性PDE4的表达因单核细胞/巨噬细胞（包括肝kupffer细胞）的酒精暴露而显着增加。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会导致对PDE4酶，PDEA，PDEA，B和D的显着上调。根据这些发现，我们假设我们假设慢性乙醇在PDE4依赖性的方式中会降低肝细胞的营地。对于酒精性肝病（ALD），没有FDA批准的疗法。使用最广泛的（标签）药物疗法是糖皮质激素和五氧化脂蛋白（PTX）。不幸的是，接受糖皮质激素治疗的AH患者的重要子集具有“类固醇耐药性”，有些患者对类固醇治疗有禁忌症。 PTX是一种仅具有弱PDE4抑制剂活性的广谱PDE抑制剂，有限研究可获得的数据表明呈阳性干预效果。因此，旨在抑制PDE4的更有定向的干预措施可能更有效。在这方面，我们最近的初步数据表明，用PDE4特异性抑制剂Rolipram的治疗显着抑制乙醇喂养动物的肝脂肪变性。我们的中心假设是，酒精暴露会增加肝细胞中cAMP降低的cAMP降解，从而降低营地水平，从而导致脂肪生成的增加和脂肪酸β氧化的降低，从而导致脂肪变性和敏感性发展，从而诱导TNF诱导的毒性。重要的是，作为推论，降低PDE4活性可能会提供重要的治疗方法。这些机械的特定目标以及翻译研究的特定目的是1）研究酒精暴露对肝细胞PDE4表达，cAMP代谢以及肝脂肪变性和损伤的发展以及2）确定PDE4亚类的作用以及PDE4抑制PDE4抑制肝脏诱导的肝脏衰减和损伤的作用。我们的未来目标是为靶向PDE4活性作为酒精患者的临床治疗提供概念基础。