Liver-specific glucocorticoid action in alcoholic liver disease.

酒精性肝病中肝脏特异性糖皮质激素的作用。

• 批准号: 9920654
• 负责人: HONG LU
• 金额: $ 23.29万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2022-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9920654
• 关键词: Acute; Adult; Adverse effects; Affect; Alcoholic Hepatitis; Alcoholic Liver Cirrhosis; Alcoholic Liver Diseases; Anti-Inflammatory Agents; Antiinflammatory Effect; Bile Acids; Binding; Cessation of life; Cholestasis; Cholic Acids; Chronic; Cirrhosis; Communities; Cytoprotection; Data; Dexamethasone; Diet; Dose; Down-Regulation; Drug Kinetics; Drug Targeting; Ethanol; Extrahepatic; Fatty acid glycerol esters; Gastrointestinal Hemorrhage; Gene Dosage; Gene Expression; Genes; Glucocorticoid Receptor; Glucocorticoids; Goals; HNF4A gene; Hepatic; Hepatocyte; Hepatorenal Syndrome; Homeostasis; Human; Hyperphagia; Impairment; In Vitro; Infection; Inflammation; Inflammatory; Knock-out; Knockout Mice; Knowledge; Literature; Liver; Liver Cirrhosis; Liver Failure; Mediating; Metabolic; Modeling; Mus; Nuclear; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Pharmacotherapy; Play; Receptor Activation; Receptor Signaling; Reporter; Resources; Role; Serum Albumin; Syndrome; Taurine Cholate; Testing; Tissues; base; bile acid transporter; cytotoxic; data mining; drug candidate; feeding; hepatocyte nuclear factor; hypocholesterolemia; improved; in vivo; innovation; liver injury; liver metabolism; macrophage; mortality; mouse model; multidisciplinary; non-alcoholic fatty liver disease; novel; novel therapeutics; pandemic disease; pharmacokinetics and pharmacodynamics; polypeptide; receptor; side effect; sugar; tool; transcriptome; uptake

Project Summary Alcoholic hepatitis (AH) is a syndrome of inflammation, cholestasis, and liver failure with worsening profile in the US. The only available drug therapy for AH that moderately improve survival is glucocorticoids (GCs), with no new drugs successfully developed for decades. The rationale of GCs is to activate the glucocorticoid receptor (GR) to block cytotoxic and inflammatory pathways in AH patients. However, GC treatment of AH causes serious side effects, largely due to GCs’ adverse effects on extrahepatic tissues. Thus, liver-specific activation of GR may markedly improve AH therapy by minimizing GC’s extrahepatic adverse effects. A prerequisite for liver-specific GR targeting for alcoholic liver disease (ALD) is to fully understand the roles of liver-specific deficiency and activation of GR in ALD pathogenesis. Our long-term goal is to develop novel therapies for ALD. Bile acid (BA)-drug conjugates have been successfully developed for liver-specific drug targeting via the liver-specific BA transporter Na+-taurocholate cotransporting polypeptide (NTCP). We have successfully synthesized two first-in-class cholic acid (CA) conjugates of dexamethasone (DEX-CA) and verified their NTCP-dependent cellular uptake and activity. The objective of this R21 proposal is to develop these novel DEX-CAs as new drug candidates for ALD, and uncover how liver-specific deficiency and activation of GR regulate hepatic gene expression, metabolic homeostasis, and ALD pathogenesis. Our data mining found that AH human livers and livers from adult mice with hepatocyte-specific knockout of GR had highly similar down-regulation of certain key GR-target cytoprotective and anti-inflammatory genes, and impaired hepatic GR signaling was associated with cholestatic liver injury in our mouse studies. The central hypothesis is that GR in hepatocytes plays a key role in protecting against AH and alcoholic cirrhosis. By decreasing the adverse effects of GCs in extrahepatic tissues and exerting cytoprotective and anti- inflammatory effects on the liver, NTCP-mediated liver-specific GR activators will be a much-improved therapy for AH and a novel therapy for alcoholic cirrhosis. Aim 1 will characterize and optimize the pharmacokinetics and pharmacodynamics of the two classes of DEX-CAs in vitro and in vivo for maximum liver-specific GR activation. Aim 2 will delineate how liver-specific gene-dosage-dependent GR deficiency and activation of GR by DEX-CA affects ALD in mouse models of AH and alcoholic cirrhosis. This proposal is highly innovative because of its conceptual advances and up-to-date approaches. This study will develop highly innovative DEX-CA conjugates as new drug candidates and the first pharmacological tool for liver- specific activation of GR. It will uncover novel roles of gene-dosage-dependent GR deficiency and liver- specific activation of GR in regulating hepatic transcriptome, metabolic homeostasis and ALD pathogenesis, and whether the DEX-CA conjugate's actions are dependent on GR in hepatocytes. This will help develop novel improved therapy for AH and alcoholic cirrhosis via liver-specific activation of GR by DEX-CAs.

项目摘要 酒精性肝炎（AH）是一种炎症、胆汁淤积和肝功能衰竭的综合征， 美方唯一可适度改善生存率的AH药物治疗是糖皮质激素（GC）， 几十年来都没有成功开发出新药。GC的原理是激活糖皮质激素 受体（GR）阻断AH患者的细胞毒性和炎症途径。然而，AH的GC治疗 会引起严重的副作用，主要是由于GC对肝外组织的不利影响。因此，肝脏特异性 GR的激活可能通过最小化GC的肝外副作用而显著改善AH治疗。一 肝脏特异性GR靶向治疗酒精性肝病（ALD）的先决条件是充分了解以下因素的作用： ALD发病机制中的肝脏特异性缺陷和GR激活。我们的长期目标是开发新颖的 治疗ALD。胆汁酸（BA）-药物偶联物已被成功开发用于肝特异性药物 通过肝特异性BA转运蛋白Na+-牛磺胆酸盐共转运多肽（NTCP）靶向。我们有 成功合成了两种一流的地塞米松胆酸（CA）缀合物（DEX-CA）和 验证了它们的NTCP依赖性细胞摄取和活性。本R21提案的目标是开发 这些新的DEX-CA作为ALD的新候选药物，并揭示了肝脏特异性缺陷和 GR的活化调节肝脏基因表达、代谢稳态和ALD发病机制。我们的数据 挖掘发现，AH人类肝脏和肝细胞特异性敲除GR的成年小鼠肝脏， 某些关键GR靶向细胞保护和抗炎基因的高度相似的下调， 在我们的小鼠研究中，受损的肝GR信号传导与胆汁淤积性肝损伤有关。中央 假设肝细胞中的GR在防止AH和酒精性肝硬化中起关键作用。通过 减轻肝外组织GCs的不良反应，发挥细胞保护和抗肿瘤作用， 由于对肝脏的炎症作用，NTCP介导的肝脏特异性GR激活剂将大大改善 AH的治疗和酒精性肝硬化的新疗法。目标1将表征和优化 两类DEX-CA在体外和体内的药代动力学和药效学， 肝脏特异性GR激活。目的2将描述肝脏特异性基因剂量依赖性GR缺乏症 在AH和酒精性肝硬化小鼠模型中，DEX-CA激活GR影响ALD。这项建议 由于其概念上的进步和最新的方法，它具有很高的创新性。这项研究将发展 高度创新的DEX-CA结合物作为新的候选药物和第一个肝脏药理学工具， 它将揭示基因剂量依赖性GR缺乏和肝脏- GR在调节肝脏转录组、代谢稳态和ALD发病机制中的特异性活化， 以及DEX-CA缀合物的作用是否依赖于肝细胞中的GR。这将有助于发展 通过DEX-CA对GR的肝脏特异性激活，对AH和酒精性肝硬化进行新的改良治疗。

项目成果

Narrative Review: Glucocorticoids in Alcoholic Hepatitis-Benefits, Side Effects, and Mechanisms.

叙事评论：酒精性肝炎，副作用和机制中的糖皮质激素。

• DOI: 10.3390/jox12040019
• 发表时间: 2022-09-21
• 期刊: Journal of xenobiotics
• 影响因子: 6
• 作者: Lu H

Crosstalk of hepatocyte nuclear factor 4a and glucocorticoid receptor in the regulation of lipid metabolism in mice fed a high-fat-high-sugar diet.

• DOI: 10.1186/s12944-022-01654-6
• 发表时间: 2022-05-25
• 期刊: LIPIDS IN HEALTH AND DISEASE
• 影响因子: 4.5
• 作者: Lu, Hong;Lei, Xiaohong;Winkler, Rebecca;John, Savio;Kumar, Devendra;Li, Wenkuan;Alnouti, Yazen
• 通讯作者: Alnouti, Yazen