The role of Sphingosine Kinase 2 in alcoholic liver disease

鞘氨醇激酶 2 在酒精性肝病中的作用

• 批准号: 9467984
• 负责人: Eric Kwun Kwong
• 金额: $ 4.4万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-25 至 2022-09-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9467984
• 关键词: ABCC1 gene; ABCG2 gene; Acute; Address; Adopted; Agonist; Alcoholic Liver Cirrhosis; Alcoholic Liver Diseases; Alcohols; Attenuated; Bacterial Translocation; Bile Acids; Binding; Cell Culture Techniques; Cell Nucleus; Cellular Stress; Chemicals; Chronic; Cirrhosis; Cytoplasm; Data; Development; Diet; Diffusion; Disease Progression; Disease model; Drug Targeting; Endotoxins; Exhibits; FDA approved; Fatty Liver; Functional disorder; Genes; Growth; Hepatic; Hepatocyte; High Fat Diet; Homeostasis; Homologous Gene; Human; In Vitro; Inflammation; Inflammation Mediators; Inflammatory Response; Injury; Intestines; Knockout Mice; Kupffer Cells; Link; Lipids; Lipopolysaccharides; Liver; Liver Failure; Liver diseases; MAP Kinase Gene; Mammalian Cell; Mediating; Membrane; Metabolic Diseases; Metabolic stress; Metabolism; Mitochondria; Molecular; Mus; National Institute on Alcohol Abuse and Alcoholism; Organoids; Oxidative Stress; Pathogenesis; Pathology; Pathway interactions; Patients; Pattern; Permeability; Play; Publishing; Regulation; Reporting; Role; Sampling; Serum; Signal Pathway; Signal Transduction; Sphingosine; Sphingosine-1-Phosphate Receptor; Stress; Testing; Therapeutic; Time; Tissues; Treatment Efficacy; Triglycerides; Wild Type Mouse; alcohol effect; autocrine; base; biological adaptation to stress; cell type; chronic liver disease; clinical application; drinking; effective therapy; endoplasmic reticulum stress; fatty acid metabolism; gut microbiota; in vivo; insight; lipid mediator; lipid metabolism; liver inflammation; liver injury; liver transplantation; macrophage; mouse model; novel; nutrient metabolism; overexpression; paracrine; response; sphingosine 1-phosphate; sphingosine kinase; transcriptome sequencing

Alcoholic liver disease (ALD) is one of the most common liver diseases worldwide characterized by the accumulation of lipids within the liver, inflammation and the possibility of progressing to cirrhosis and liver failure. More importantly, there are currently no effective treatments for ALD and liver transplantation remains the only therapeutic option for end stage liver disease. Previous studies have shown that ALD is a result of a combination of endoplasmic reticulum (ER) stress, lipid metabolism dysregulation and inflammation. It has been previously reported that alcohol disrupts gut microbiota homeostasis and causes increased endotoxins that contribute to the pathology of ALD. However, the detailed mechanism(s) underlying ALD and disease progression is poorly understood. We have discovered that sphingosine kinase 2 (SphK2) deficient (SphK2-/-) mice on an alcohol diet exhibit increased steatosis and inflammation compared to wild type mice. Sphingosine 1-phosphate receptor 2 (S1PR2) and SphK2 have been previously shown to play a key role in nutrient metabolism and signaling. However, their roles in alcohol-induced liver injury have not been characterized. The overall objective of this project is to determine the molecular mechanism(s) by which disruption of S1PR2- mediated SphK2 signaling contributes to ALD. Aim 1. First, we will determine the role of S1PR2 and SphK2 in alcohol-induced liver injury. We will examine the effects of alcohol on primary hepatocytes and Kupffer cells derived from S1PR2 deficient (S1PR2-/-) and SphK2-/- mice. We will examine various pathways and mechanisms of injury including hepatic lipid metabolism dysregulation, ER stress and inflammation. For in vivo studies, we will adopt the acute on chronic alcohol mouse model from NIAAA that recapitulates the drinking pattern of human alcoholic liver disease patients to study the effects of S1PR2 and SphK2 deficiency in ALD. We will further characterize the expression patterns of S1PR2 and SphK2 in human ALD liver samples. Aim 2. Second, we will identify potential mechanisms by which S1PR2 and SphK2 protect against alcohol-induced liver injury. We will examine various cellular stress pathways and the role of S1PR2 and SphK2 in regulating inflammatory mediators. Finally, we will evaluate the therapeutic potential of targeting the S1PR2/SphK2- mediated signaling pathway using an S1PR2 chemical agonist CYM-5520 to attenuate alcohol-induced liver injury. Accomplishing these aims could provide important information on the development of effective treatments and drug targets against ALD.

酒精性肝病（ALD）是世界范围内最常见的肝脏疾病之一，其特征是 肝脏内脂质积聚、炎症以及进展为肝硬化和肝脏的可能性 失败。更重要的是，目前ALD尚无有效治疗方法，肝移植仍待实现 终末期肝病的唯一治疗选择。先前的研究表明，ALD 是由于 内质网（ER）应激、脂质代谢失调和炎症的组合。它有 此前有报道称，酒精会破坏肠道微生物群稳态并导致内毒素增加 有助于 ALD 的病理学。然而，ALD 和疾病的详细机制 人们对进展知之甚少。我们发现鞘氨醇激酶 2 (SphK2) 缺陷 (SphK2-/-) 与野生型小鼠相比，饮酒的小鼠表现出更多的脂肪变性和炎症。鞘氨醇 1-磷酸受体 2 (S1PR2) 和 SphK2 先前已被证明在营养中发挥关键作用 代谢和信号传导。然而，它们在酒精性肝损伤中的作用尚未得到表征。这 该项目的总体目标是确定破坏 S1PR2- 的分子机制 介导的 SphK2 信号传导有助于 ALD。目标 1. 首先，我们将确定 S1PR2 和 SphK2 在 酒精引起的肝损伤。我们将检查酒精对原代肝细胞和库普弗细胞的影响 源自 S1PR2 缺陷型 (S1PR2-/-) 和 SphK2-/- 小鼠。我们将研究各种途径并 损伤机制包括肝脂质代谢失调、内质网应激和炎症。对于体内 研究中，我们将采用 NIAAA 的急性慢性酒精小鼠模型来概括饮酒情况 人类酒精性肝病患者的模式，以研究 S1PR2 和 SphK2 缺乏对 ALD 的影响。 我们将进一步表征 S1PR2 和 SphK2 在人 ALD 肝脏样本中的表达模式。目标2。 其次，我们将确定 S1PR2 和 SphK2 预防酒精诱导的潜在机制 肝损伤。我们将研究各种细胞应激途径以及 S1PR2 和 SphK2 在调节中的作用 炎症介质。最后，我们将评估针对 S1PR2/SphK2- 的治疗潜力 使用 S1PR2 化学激动剂 CYM-5520 介导的信号通路来减轻酒精诱导的肝损伤 受伤。实现这些目标可以为制定有效的 针对 ALD 的治疗方法和药物靶点。