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）是美国肝衰竭的主要原因之一，占4％ 全球死亡率。鞘脂，一种脂质类信号传导特性，已与许多 肝病。鞘脂由丝氨酸棕榈酰转移酶形成，一种杂二聚体酶组成 SPTLC1和SPLTC2的亚基。该异二聚体结合了丝氨酸和棕榈酰辅酶A以产生 二氢磷酸化菌素是生成所有下游鞘脂的支架（例如，神经酰胺，， 鞘磷脂，糖磷脂，1-磷酸盐等）。尽管它们在病理学中含义 所有真核细胞都需要鞘脂。但是，先前确定的新型鞘脂池 被确定。这些脂质来自具有新型SPT亚基SPTLC3的SPTLC1的二聚化。我们在这里显示 该SPTLC3是在ALD的小鼠模型中诱导的，导致非典型鞘脂的增加，我们显示 以潜在的保护方式调节多种途径。因此，我们建议规范 源自SPTLC1/2异二聚体的鞘脂是体内稳态和/或在肝脏病理学中起作用的 肝侮辱SPTLC3是诱导的，以保护方式改变了细胞内鞘脂。这会 提供了针对非典型，SPTLC3衍生的鞘脂的治疗干预的机会， 使体内稳态鞘脂池完整。 我们假设背后的科学前提是，可以针对鞘脂代谢 或反向酒精肝损伤。我们的假设是损伤诱导了这些非典型鞘脂或子集 它以这种方式激活调节自噬/线索的途径，以加快从 由乙醇代谢造成的线粒体损害，以及诱导其产量的线粒体损害会减轻损伤。 这将在3个目标中进行测试：1-确定肝细胞中SPTLC3上调的机制，以及如何 这改变了鞘脂曲线，2建立SPTLC3和D16-Sphingolipids在线粒体中的作用， 线粒体功能和核受体转录因子的调节3-评估 酒精以肝细胞特异性SPTLC3敲除小鼠为食。该项目的深远目标是 基于操纵肝细胞中非典型鞘脂的代谢的ALD的未来疗法。