Sphingolipids in alcoholic liver disease

酒精性肝病中的鞘脂

• 批准号: 10608594
• 负责人: PHILLIP B HYLEMON
• 金额: $ 52.31万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608594
• 关键词: Acute; Alcoholic Hepatitis; Alcoholic Liver Diseases; Alcohols; Alveolar Macrophages; Bacterial Translocation; Bile Acids; Cell Nucleus; Chronic; Cirrhosis; Clinical; Cytoplasm; Data; Development; Disease; Disease Progression; Epithelial Cells; FDA approved; Fatty Acids; Fatty Liver; G-Protein-Coupled Receptors; Genes; Genetic Transcription; Growth; HDAC1 gene; Hepatic; Hepatocyte; Heterogeneity; High Fat Diet; Histone Acetylation; Histone Deacetylase Inhibitor; ITGAM gene; Inflammatory; Inflammatory Response; Intestinal permeability; Intestines; Knock-out; Knockout Mice; Leaky Gut; Ligands; Link; Lipids; Liver Fibrosis; LoxP-flanked allele; MAPK3 gene; Macrophage; Mammalian Cell; Mediating; Metabolic Diseases; Mitochondria; Molecular; Morbidity - disease rate; Mus; Myeloid Cells; National Institute on Alcohol Abuse and Alcoholism; Nuclear; Organelles; Organoids; Pathogenesis; Patients; Phospholipase; Play; Predisposition; Production; Proto-Oncogene Proteins c-akt; Reporting; Role; SPHK1 enzyme; Signal Pathway; Signal Transduction; Signaling Molecule; Sphingolipids; Sphingosine; Sphingosine-1-Phosphate Receptor; Stimulator of Interferon Genes; Stress; Testing; Tissues; alcohol response; base; bile acid metabolism; cell type; chronic liver disease; clinical application; curative treatments; feeding; global health; glucose metabolism; gut microbiome; gut-liver axis; inhibitor; intestinal barrier; intestinal epithelium; lipid metabolism; liver inflammation; liver injury; liver transplantation; mortality; mouse model; novel; novel therapeutic intervention; novel therapeutics; problem drinker; response; single nucleus RNA-sequencing; sphingosine 1-phosphate; sphingosine kinase; systemic inflammatory response; therapeutically effective; transcriptome sequencing

Alcoholic liver disease (ALD) remains the most common chronic liver disease worldwide. Despite extensive studies, no FDA-approved therapy is available for any stage of ALD due to the limited understanding of disease pathogenesis. Therefore, the unmet need to identify novel targets for developing effective therapeutics against ALD is urgent. Alcohol not only alters hepatic lipid and bile acid metabolism but also disrupts the gut microbiome and intestinal barrier function, which results in a leaky gut and bacterial translocation as well as activation of systemic and hepatic inflammation. We have previously reported that conjugated bile acids activate sphingosine- 1 phosphate receptor 2 (S1PR2), which further activates ERK1/2 and AKT. S1P is one of the most studied sphingolipids and is synthesized from sphingosine by either sphingosine kinase 1 (SphK1) or SphK2. S1P can regulate various fundamental cellular responses either as an intracellular signaling molecule or a ligand for five GPCRs, S1PR1-5. SphK2-generated nuclear S1P is a potent natural inhibitor of histone deacetylases (HDAC1/2). Activation of the stimulator of interferon genes (STING) also has been identified as critical signaling in ALD. A recent study reported that SphK2-mediated production of nuclear S1P in CD11b+ macrophages is a strong inhibitor of STING and suppresses the inflammatory response in alveolar macrophages. We have reported that SphK2-/- mice developed more severe fatty liver and hepatic injury in the NIAAA ALD mouse model. Hepatic SphK2 expression levels were markedly reduced in both ALD cirrhotic patients and ALD mouse models. Alcohol-feeding significantly increased intestinal permeability and bacterial translocation in SphK2-/- mice. Our preliminary data further showed that 1) alcohol-feeding induced more severe liver injury in the global SphK2-/- mice than hepatocyte-specific SphK2 knockout (SphK2Hep-/-); 2) intestinal epithelial cell-specific SphK2 knockout (SphK2IEC-/-) mice were more prone to alcohol-induced liver injury compared to SphK2fl/fl mice; 3) RNAseq analysis showed that chronic alcohol feeding significantly disrupted hepatic sphingolipid, fatty acid, and bile acid metabolism and activated inflammatory and fibrotic responses; 4) deletion of SphK2 inhibited the growth of intestinal organoids. Based on these key findings, we HYPOTHESIZE that disruption of SphK2/S1P-mediated signaling pathways in the gut-liver axis plays a critical role in alcohol-induced liver injury. Two specific aims are proposed to test the hypothesis. 1) To investigate the role and mechanisms of SphK2 in modulating hepatic lipid metabolism and inflammatory response under the conditions of acute and chronic alcohol-induced stress. 2): To define the role of SphK2 in modulating intestinal barrier function and to identify the cellular mechanisms by which SphK2 modulates the gut liver axis in response to alcohol-induced stress. Accomplishing these specific aims will significantly advance our current understanding of the tissue and cell-type-specific roles of SphK2/S1P-mediated signaling pathways in ALD, which holds great promise for developing novel therapeutic interventions not only for ALD but also for other related metabolic diseases.

酒精性肝病（ALD）仍然是全世界最常见的慢性肝病。尽管广泛 研究表明，由于对疾病的了解有限，FDA 尚未批准针对 ALD 任何阶段的治疗方法 发病。因此，确定新靶点以开发有效疗法的需求尚未得到满足 ALD 很紧急。酒精不仅会改变肝脏脂质和胆汁酸代谢，还会破坏肠道微生物组 和肠道屏障功能，导致肠漏和细菌易位以及激活 全身和肝脏炎症。我们之前曾报道过，结合胆汁酸可激活鞘氨醇- 1 磷酸受体 2 (S1PR2)，进一步激活 ERK1/2 和 AKT。 S1P 是研究最多的之一 鞘脂，由鞘氨醇通过鞘氨醇激酶 1 (SphK1) 或 SphK2 合成。 S1P可以 作为细胞内信号分子或五种配体调节各种基本细胞反应 GPCR，S1PR1-5。 SphK2 生成的核 S1P 是组蛋白脱乙酰酶的有效天然抑制剂 (HDAC1/2)。干扰素基因刺激物 (STING) 的激活也被认为是关键信号传导 在酒精性肝病中。最近的一项研究报告称，SphK2 介导的 CD11b+ 巨噬细胞中核 S1P 的产生是一种 STING 的强抑制剂并抑制肺泡巨噬细胞的炎症反应。我们有 报道称，SphK2-/- 小鼠在 NIAAA ALD 小鼠模型中出现更严重的脂肪肝和肝损伤。 ALD 肝硬化患者和 ALD 小鼠模型中肝脏 SphK2 表达水平均显着降低。 酒精喂养显着增加了 SphK2-/- 小鼠的肠道通透性和细菌易位。我们的 初步数据进一步显示，1）饮酒导致全球SphK2-/-中更严重的肝损伤 比肝细胞特异性 SphK2 敲除 (SphK2Hep-/-) 的小鼠； 2）肠上皮细胞特异性SphK2敲除 与 SphK2fl/fl 小鼠相比，(SphK2IEC-/-) 小鼠更容易出现酒精引起的肝损伤； 3)RNA测序 分析表明，长期饮酒会显着破坏肝脏鞘脂、脂肪酸和胆汁酸 新陈代谢以及激活的炎症和纤维化反应； 4）SphK2的缺失抑制了生长 肠道类器官。基于这些关键发现，我们假设 SphK2/S1P 介导的破坏 肠-肝轴信号通路在酒精性肝损伤中发挥着关键作用。两个具体目标是 建议检验假设。 1) 探讨SphK2调节肝脂的作用及机制 急性和慢性酒精应激条件下的代谢和炎症反应。 2): 至 定义 SphK2 在调节肠道屏障功能中的作用并确定其细胞机制 SphK2 调节肠肝轴以应对酒精引起的应激。实现这些具体目标将 显着推进了我们目前对 SphK2/S1P 介导的组织和细胞类型特异性作用的理解 ALD 中的信号通路，不仅为开发新的治疗干预措施带来了巨大的希望 ALD还适用于其他相关的代谢性疾病。