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）仍然是全球最常见的慢性肝病。尽管进行了广泛 研究，由于对疾病的了解有限，没有FDA批准的治疗方法可用于ALD的任何阶段 发病机制因此，未满足的需要是鉴定用于开发抗肿瘤的有效治疗剂的新靶点。 AD是紧急的。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，导致肠道渗漏和细菌移位以及激活 全身和肝脏炎症。我们以前报道过结合胆汁酸激活鞘氨醇- 1磷酸盐受体2（S1 PR 2），其进一步激活ERK 1/2和AKT。S1 P是研究最多的一种 鞘氨醇是鞘脂的一种，由鞘氨醇激酶1（SphK 1）或SphK 2合成。S1 P可以 作为细胞内信号分子或五种细胞因子的配体， GPCR，S1PR 1 -5。SphK 2产生的核S1 P是组蛋白去乙酰化酶的有效天然抑制剂 （HDAC 1/2）。干扰素基因刺激因子（STING）的激活也被认为是关键的信号传导 在ALD。最近的一项研究报道，在CD 11b+巨噬细胞中，SphK 2介导的核S1 P的产生是一个重要的机制。 STING的强抑制剂并抑制肺泡巨噬细胞中的炎症反应。我们有 报道，SphK 2-/-小鼠在NIAAA ALD小鼠模型中发生更严重的脂肪肝和肝损伤。 肝SphK 2表达水平在ALD患者和ALD小鼠模型中均显著降低。 酒精喂养显着增加肠道通透性和细菌易位SphK 2-/-小鼠。我们 初步数据进一步表明，1）酒精喂养在全球SphK 2-/-中诱导了更严重的肝损伤， 小鼠比肝细胞特异性SphK 2敲除（SphK 2 Hep-/-）; 2）肠上皮细胞特异性SphK 2敲除 与SphK 2fl/fl小鼠相比，SphK 2 IEC-/-小鼠更容易发生酒精诱导的肝损伤; 3）RNAseq 分析表明，长期饮酒显著破坏了肝脏鞘脂、脂肪酸和胆汁酸 代谢和激活炎症和纤维化反应; 4）SphK 2的缺失抑制了细胞的生长， 肠类器官基于这些关键发现，我们假设SphK 2/S1 P介导的 肠-肝轴中的信号传导途径在酒精诱导的肝损伤中起关键作用。两个具体目标是 来检验这个假设。1)探讨SphK 2对肝脏脂质的调节作用及其机制 在急性和慢性酒精诱导的应激条件下的代谢和炎症反应。2）：至 确定SphK 2在调节肠屏障功能中的作用，并确定其细胞机制， SphK 2调节肠肝轴响应酒精诱导的应激。实现这些具体目标将 显著推进我们目前对SphK 2/S1 P介导的组织和细胞类型特异性作用的理解。 酒精性肝脏疾病中的信号通路，不仅为开发新型治疗干预措施带来了巨大希望， ALD也适用于其他相关的代谢疾病。