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。

基本信息

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
项目类别：
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

项目摘要

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，胆汁淤积和肝衰竭的综合征，遗憾美国。适度提高生存率的AH唯一可用的药物治疗是糖皮质激素（GCS），几十年来，没有成功开发的新药。 GC的理由是激活糖皮质激素 AH患者的接收器（GR）阻断细胞毒性和炎症途径。但是，GC治疗AH 引起严重的副作用，这在很大程度上是由于GCS对脑外组织的不良影响。那，特定于肝 GR的激活可能会通过最大程度地减少GC的外膜外不良反应来显着改善AH治疗。一个肝特异性GR靶向酒精性肝病（ALD）的先决条件是完全了解肝特异性缺乏和ALD发病机理中GR的激活。我们的长期目标是发展小说 ALD的疗法。胆汁酸（BA） - 药物结合物已成功开发为肝特异性药物通过肝特异性BA转运蛋白Na+-Taurochaly共转运多肽（NTCP）靶向。我们有成功合成了地塞米松（DEX-CA）和验证了他们的NTCP依赖性细胞摄取和活性。该R21提案的目的是发展这些新型的DEX-CA作为ALD的新药候选者，并发现了肝脏特异性缺乏和如何 GR的激活调节肝基因表达，代谢稳态和ALD发病机理。我们的数据矿业发现，AH人类肝脏和肝脏的肝细胞特异性敲除GR 高度相似的某些关键GR靶向细胞保护和抗炎基因的下调，以及在我们的小鼠研究中，肝脏GR信号受损与胆汁淤积性肝损伤有关。中央假设是，肝细胞中的GR在保护AH和酒精性肝硬化中起着关键作用。经过减少GC在脑外组织中的不良反应，并施加细胞保护和抗 NTCP介导的肝脏特异性GR激活剂对肝脏的炎症作用将是一种备受改善的 AH的治疗和一种新颖的酒精性肝硬化疗法。 AIM 1将表征和优化两类dex-CAS的药代动力学和药效学在体外和体内最大肝特异性GR激活。 AIM 2将描述肝脏特异性基因dosage GR缺乏症如何 DEX-CA对GR的激活影响AH和酒精性肝硬化的小鼠模型中的ALD。这个建议由于其概念上的进步和最新的方法，因此具有很高的创新性。这项研究将发展高度创新的DEX-CA偶联是新药候选者，也是肝脏的第一个药物工具 - GR的特定激活。它将发现基因d依赖性GR缺乏和肝的新作用 GR在调节中的特异性激活肝转录组，代谢稳态和ALD发病机理， DEX-CA结合的作用是否取决于肝细胞中的GR。这将有助于发展通过DEX-CAS对GR的肝脏特异性激活，新颖的AH和酒精性肝硬化的治疗方法改善了治疗。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

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
通讯作者：
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