Atypical sphingolipids in alcoholic liver disease

酒精性肝病中的非典型鞘脂

• 批准号: 10453295
• 负责人: Lauren Ashley Cowart
• 金额: $ 20.86万
• 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: 2023-04-20 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10453295
• 关键词: Albumins; Alcohol consumption; Alcoholic Liver Diseases; Alcoholic liver damage; Alcohols; Anabolism; Area; Attenuated; Autophagocytosis; Beverages; Biochemical; Carbon; Cardiovascular Diseases; Cells; Ceramides; Cessation of life; Coenzyme A; Complex; Data; Development; Dihydrosphingosine; Dimerization; Enzymes; Ethanol; Ethanol Metabolism; Eukaryota; Eukaryotic Cell; Exploratory/Developmental Grant; Future; Generations; Genetic Transcription; Glycosphingolipids; Goals; Heavy Drinking; Hepatic; Hepatocyte; In Vitro; Injury; Knockout Mice; Laboratories; Ligands; Lipids; Liver; Liver Failure; Liver diseases; Logic; LoxP-flanked allele; Mediating; Metabolic Pathway; Metabolism; Methods; Mitochondria; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Receptors; Organ; Outcome; Palmitates; Palmitoyl Coenzyme A; Pathology; Pathway interactions; Production; Property; Proteins; Public Health; Recovery; Regulation; Reporting; Research Project Grants; Respondent; Role; Serine; Signal Pathway; Signal Transduction; Site; Sphingolipids; Sphingomyelins; Surveys; Techniques; Testing; Therapeutic; Therapeutic Intervention; Tissues; Transcription Factor 3; Transferase; Up-Regulation; Vertebral column; addiction; alcohol exposure; alcohol response; base; cohort; constitutive expression; experimental study; feeding; hepatocyte injury; in vivo; injury recovery; interest; lipidomics; liver injury; mortality; mouse model; novel; preference; prevent; scaffold; serine palmitoyltransferase; sphingosine 1-phosphate; statistics; tool; transcription factor

Alcoholic liver disease (ALD) is one of the leading causes of liver failure in the U.S., and accounts for 4% of mortality worldwide. Sphingolipids, a lipid class bearing signaling properties, have been implicated in numerous liver pathologies. Sphingolipids are formed by serine palmitoyltransferase, a heterodimeric enzyme composed of the subunits Sptlc1 and Spltc2. This heterodimer combines serine and palmitoyl-CoA to generate dihydrosphingosine, which serves as a scaffold for generation of all downstream sphingolipids (e.g., ceramides, sphingomyelins, glycosphingolipids, sphingosine-1-phosphate, etc.). Despite their implication in pathology, sphingolipids are required by all eukaryotic cells. However, a previously identified novel pool of sphingolipids were identified. These lipids arise from a dimerization of Sptlc1 with a novel SPT subunit, Sptlc3. Here we show that Sptlc3 is induced in a mouse model of ALD leading to an increase in atypical sphingolipids, which we show to regulate several pathways in a potentially protective manner. Therefore, we propose that the canonical sphingolipids derived from Sptlc1/2 heterodimer are homeostatic and/or play a role in liver pathology, but in some hepatic insults Sptlc3 is induced, changing the intracellular sphingolipidome in a protective manner. This would present the opportunity for therapeutic intervention directed toward atypical, Sptlc3-derived sphingolipids, leaving the homeostatic sphingolipid pool intact. The scientific premise behind our hypothesis is that sphingolipid metabolism could be targeted to prevent or reverse alcoholic liver injury. Our hypothesis is that injury induces these atypical sphingolipids, or a subset thereof, which activate pathways regulating autophagy/mitophagy, in a manner that expedites recovery from mitochondrial damage caused by metabolism of ethanol, and that inducing their production will attenuate injury. This will be tested in 3 aims: 1- determine the mechanism of SPTLC3 upregulation in hepatocytes, and how this alters sphingolipid profiles, 2-establish the role(s) of SPTLC3 and d16-sphingolipids in mitophagy, mitochondrial function, and regulation of nuclear receptor transcription factors 3- assess the impact of alcohol feeding on the hepatocyte-specific Sptlc3 knockout mouse. The far-reaching goal of this project is to pursue future treatments for ALD based on manipulating metabolism of atypical sphingolipids in hepatocytes.

酒精性肝病(ALD)是美国肝功能衰竭的主要原因之一，占美国 全球范围内的死亡率。鞘磷脂是一类具有信号特性的脂类，已被认为与许多 肝脏病理检查。鞘磷脂是由丝氨酸棕榈酰转移酶形成的，丝氨酸棕榈酰转移酶是一种异二聚体酶，由 Sptlc1和Spltc2亚基。这种杂二聚体结合丝氨酸和棕榈酰辅酶A生成 二氢鞘氨醇，其用作生成所有下游鞘脂(例如，神经酰胺， 鞘磷脂、鞘糖脂、鞘氨醇-1-磷酸等)。尽管它们在病理学上有意义， 鞘磷脂是所有真核细胞所必需的。然而，之前发现的一组新的鞘脂 都被确认了。这些脂质是由Sptlc1与新的SPT亚基Sptlc3二聚化而成的。我们在这里展示 在ALD的小鼠模型中，Sptlc3被诱导，导致非典型鞘脂的增加，这是我们证明的 以潜在的保护性方式调节几条通路。因此，我们提出，规范的 Sptlc1/2异二聚体衍生的鞘磷脂是稳态的和/或在肝脏病理中发挥作用，但在某些情况下 肝脏损伤Sptlc3被诱导，以保护性的方式改变细胞内的鞘磷脂。这将会 提供了针对非典型的Sptlc3衍生的鞘脂的治疗干预的机会， 保持体内平衡的鞘脂池完好无损。 我们假设背后的科学前提是鞘磷脂新陈代谢可以靶向预防 或逆转酒精性肝损伤。我们的假设是，损伤导致了这些非典型的鞘脂，或一个子集 激活调节自噬/有丝分裂吞噬的通路，以加速从 乙醇代谢引起的线粒体损伤，诱导其产生将减轻损伤。 这将在三个目标上进行测试：1-确定SPTLC3在肝细胞中上调的机制，以及如何 这改变了鞘脂谱，2-确定SPTLC 3和D16-鞘脂在有丝分裂中的作用(S)， 线粒体功能和核受体转录因子3的调节--评估 酒精喂养肝细胞特异性Sptlc3基因敲除小鼠。这个项目的深远目标是 通过调控非典型鞘脂在肝细胞中的代谢，探索ALD的未来治疗方法。