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病之一，其特征在于： 肝脏内脂质积聚，炎症和进展为肝硬化和肝脏的可能性 失败更重要的是，目前尚无有效治疗ALD和肝移植残留的方法 终末期肝病的唯一治疗选择。以前的研究表明，ALD是一种 内质网（ER）应激，脂质代谢失调和炎症的组合。它有 先前有报道称，酒精会破坏肠道微生物群的稳态，导致内毒素增加， 导致酒精性肝病的病理学改变然而，ALD和疾病的详细机制 进展情况知之甚少。我们已经发现鞘氨醇激酶2（SphK2）缺陷（SphK2-/-） 与野生型小鼠相比，酒精饮食的小鼠表现出增加的脂肪变性和炎症。氨醇 1-磷酸盐受体2（S1PR2）和SphK2先前已被证明在营养物质中起关键作用。 代谢和信号传导。然而，其在酒精诱导的肝损伤中的作用尚未得到表征。的 本项目的总体目标是确定S1PR2- 介导的SphK2信号转导有助于ALD。目标1.首先，我们将确定S1PR2和SphK2在 酒精性肝损伤我们将研究酒精对原代肝细胞和枯否细胞的影响 来源于S1PR2缺陷（S1PR2-/-）和SphK2-/-小鼠。我们将研究各种途径， 损伤机制包括肝脏脂质代谢失调、内质网应激和炎症反应。用于体内 研究中，我们将采用NIAAA的急性慢性酒精小鼠模型，重现饮酒 研究S1PR2和SphK2缺陷在ALD中的作用。 我们将进一步表征人ALD肝脏样品中S1PR2和SphK2的表达模式。目标二。 其次，我们将确定S1PR2和SphK2保护酒精诱导的细胞凋亡的潜在机制。 肝损伤我们将研究各种细胞应激途径以及S1PR2和SphK2在调节细胞凋亡中的作用。 炎症介质。最后，我们将评估靶向S1PR2/SphK2的治疗潜力。 使用S1PR2化学激动剂CYM-5520介导的信号传导途径来减弱酒精诱导的肝脏 损伤实现这些目标可以为发展有效的 针对ALD的治疗和药物靶点。