Lipidated Amino Acids in Cardiometabolic Diseases

心血管代谢疾病中的脂化氨基酸

• 批准号: 10503007
• 负责人: Oren Shalom Rom
• 金额: $ 32.69万
• 依托单位: LOUISIANA STATE UNIV HSC SHREVEPORT
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-02 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10503007
• 关键词: Acids; Address; Advanced Development; Affect; Amides; Amino Acids; Arterial Fatty Streak; Atherosclerosis; Attention; Automobile Driving; Biological Assay; Cardiometabolic Disease; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Chronic; Clinical; Data; Dependence; Development; Diet; Disease; Dyslipidemias; Energy Metabolism; Enzymes; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Fibrosis; Genes; Genetic; Genetic Transcription; Healthcare Systems; Hepatic; Hepatocyte; Histologic; Human; In Vitro; Individual; Inflammation; Inflammatory; Intervention; Lesion; Leucine; Ligands; Light; Link; Lipids; Liver; Liver Fibrosis; Lobular; Luciferases; Mediating; Metabolic; Metabolic Pathway; Modeling; Mouse Strains; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; PPAR alpha; PTGS1 gene; PTGS2 gene; Pathway interactions; Patients; Pharmacology; Population; Regulation; Risk; Risk Factors; Role; Sampling; Signal Pathway; Signaling Molecule; Testing; Tissues; Up-Regulation; Variant; Weight Gain; Work; amino acid metabolism; base; cardiometabolic risk; chemokine; chronic liver disease; dietary; drug candidate; drug development; fatty acid oxidation; gain of function; genetic variant; genome wide association study; genome-wide; hepatocyte injury; in vivo; in vivo Model; indexing; lipid metabolism; long chain fatty acid; macrophage; metabolomics; monocyte; mortality; mouse model; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel therapeutic intervention; novel therapeutics; overexpression; recruit; transcriptomics

PROJECT SUMMARY/ABSTRACT Non-alcoholic fatty liver disease (NAFLD) affects 25% of the global population at a substantial burden to the health care system. Despite significant advances in our understanding of the underlying causes and considerable efforts in drug development, no pharmacological therapy currently exists for this disease. Accelerated atherosclerosis, independent of traditional risk factors, is the major cause of death in patients with NAFLD, particularly in those with the more severe non-alcoholic steatohepatitis (NASH). Thus, there is an urgent clinical need to identify new pathways for simultaneous targeting of NASH and atherosclerosis. Imbalanced lipid metabolism and dysregulated amino acid metabolism are emerging as common features in both NASH and atherosclerosis, although their crosstalk has not received much attention. Lipidated amino acids or N-acyl amino acids (NAAs) have emerged as endogenous signaling molecules in which an amide bond links an amino acid to the acyl moiety of a long-chain fatty acid. Yet, little is known about the metabolic regulation of NAAs, particularly in cardiometabolic diseases. Our preliminary data uncovered that the liver is a major hub for NAA metabolism. Unbiased transcriptomics revealed suppression of known NAA biosynthetic genes (GLYAT, ADH7 and PM20D1) and upregulation of degradative genes (PAM, PTGS1 and PTGS2) in livers from humans and mice with NASH, concomitant with marked reduction of NAAs, as determined by metabolomics. Hepatic NAAs inversely correlated with NASH and inflammatory indices. Importantly, chronic administration of N-oleoyl leucine (C18:1-Leu), as proof-of-concept, protected against diet-induced NASH, independent of changes in systemic energy metabolism. This was associated with induction of hepatic peroxisome proliferator-activated receptor α (PPARα)/fatty acid oxidation (FAO), suppression of C-C motif chemokine ligand 2 (CCL2) and reduced hepatic macrophages and fibrosis. In atherosclerotic mice, C18:1-Leu reduced lesional macrophages and atherosclerosis, while concurrently lowering hepatic steatosis and CCL2. Thus, our findings support the potential of NAAs for the simultaneous treatment of NASH and atherosclerosis. This project will address the central hypothesis that lipid overload and ensuing inflammation inhibit hepatic NAA formation, while NAAs stimulate hepatic PPARα and suppress CCL2, simultaneously reducing NASH and atherosclerosis. Aim 1 will determine the mechanisms driving suppression of NAAs in NASH and atherosclerosis using in vitro and in vivo models of loss- and gain-of- function of NAA metabolic genes and will define genetic variants in these genes linking both diseases in GWAS and human liver samples. Aim 2 will define NAAs as a potential therapy for NASH, thereby atherosclerosis, and its dependence on PPARα-mediated hepatic FAO and suppression of CCL2 using new liver-specific and dietary mouse models combined with in vitro approaches. This work will characterize a newly identified metabolic pathway linking NASH and atherosclerosis and provide mechanistic data to accelerate the development of NAAs as a simultaneous treatment for these diseases, thus addressing a significant unmet clinical need.

项目摘要/摘要 非酒精性脂肪肝疾病（NAFLD）影响了全球25％的人口，并在大量燃烧中影响 医疗保健系统。尽管我们对基本原因和相当大的理解取得了重大进展 药物开发方面的努力，目前尚无药物疗法的这种疾病。加速 与传统危险因素无关的动脉粥样硬化是NAFLD患者的主要死亡原因， 特别是在患有更严重的非酒精性脂肪性肝炎（NASH）的人中。那是紧急临床 需要确定简单靶向纳什和动脉粥样硬化的新途径。脂质不平衡 代谢和失调的氨基酸代谢在纳什和 动脉粥样硬化，尽管他们的串扰并没有得到太多关注。脂化氨基酸或N-酰基氨基 酸（NAA）已成为内源信号分子，其中酰胺键将氨基酸连接到 长链脂肪酸的酰基部分。然而，关于NAA的代谢调节知之甚少，特别是 在心脏代谢性疾病中。我们的初步数据发现肝脏是NAA代谢的主要枢纽。 无偏的转录组学揭示了已知的NAA生物合成基因的抑制（Glyat，ADH7和PM20D1） 和nash的人类和小鼠的肝脏中降解基因（PAM，PTGS1和PTGS2）的上调 由代谢组学确定的NaAS显着降低。肝NAAS成反比 带有纳什和炎症指数。重要的是，长期给予N-烯酰亮氨酸（C18：1-LEU），AS 概念证明，免受饮食诱导的NASH的保护，与系统性能量代谢的变化无关。 这与肝过氧化物体增殖物激活受体α（PPARα）/脂肪酸的诱导有关 氧化（FAO），C-C基序趋化因子配体2（CCL2）的抑制作用，并减少肝巨噬细胞和减少 纤维化。在动脉粥样硬化小鼠中，C18：1- leu降低了病毒巨噬细胞和动脉粥样硬化，而动脉粥样硬化 同时降低肝脂肪变性和CCL2。这，我们的发现支持NAA的潜力 简单治疗纳什和动脉粥样硬化。该项目将解决脂质的中心假设 超负荷并确保炎症抑制肝NAA的形成，而NaAS刺激肝PPARα和 抑制CCL2，只是减少纳什和动脉粥样硬化。 AIM 1将确定机制 使用体外和体内损失模型和在体内驱动NAA和动脉粥样硬化抑制NAA NAA代谢基因的功能，并将在这些基因中定义遗传变异，这些基因连接了GWAS中的两种疾病 和人肝样品。 AIM 2将NAAS定义为NASH的潜在疗法，从而将动脉粥样硬化和 它依赖于PPARα介导的肝杆菌和使用新肝脏特异性和饮食的CCL2抑制 小鼠模型与体外方法结合使用。这项工作将描述新的代谢 连接纳什和动脉粥样硬化并提供机械数据以加速NAAS的途径 作为这些疾病的简单治疗方法，因此可以满足未满足的临床需求。