Lipidated Amino Acids in Cardiometabolic Diseases

心血管代谢疾病中的脂化氨基酸

• 批准号: 10633254
• 负责人: Oren Shalom Rom
• 金额: $ 45.26万
• 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/10633254
• 关键词: Acceleration; 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; Leucine; Ligands; Link; Lipids; Liver; Liver Fibrosis; Lobular; Luciferases; Macrophage; Mediating; Metabolic; Metabolic Pathway; Modeling; Mouse Strains; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; PPAR alpha; PTGS1 gene; PTGS2 gene; Pathway interactions; Patients; Population; Regulation; Risk; Risk Factors; Role; Sampling; Signal Pathway; Signaling Molecule; Testing; Tissues; Up-Regulation; Variant; Weight Gain; Work; amino acid metabolism; 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; loss of function; metabolomics; monocyte; mortality; mouse model; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel therapeutic intervention; novel therapeutics; overexpression; pharmacologic; 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 非酒精性脂肪性肝病（NAFLD）影响全球25%的人口，对全球人口造成巨大负担。 医疗保健系统。尽管我们在理解根本原因和相当大的进步 尽管在药物开发方面做出了努力，但目前还不存在针对这种疾病的药物治疗。加速 独立于传统危险因素的动脉粥样硬化是NAFLD患者死亡的主要原因， 特别是在患有更严重的非酒精性脂肪性肝炎（NASH）的患者中。因此，迫切需要临床 需要确定同时靶向NASH和动脉粥样硬化的新途径。血脂失衡 代谢和失调的氨基酸代谢正在成为NASH和NASH中的共同特征。 动脉粥样硬化，虽然他们的串扰没有得到太多的关注。脂化氨基酸或N-酰基氨基 氨基酸（NAAs）已经作为内源性信号分子出现，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NAAs的代谢调节知之甚少， 心脏代谢性疾病我们的初步数据揭示了肝脏是NAA代谢的主要枢纽。 无偏转录组学显示已知NAA生物合成基因（GLYAT，ADH 7和PM 20 D1）的抑制 以及来自患有NASH的人和小鼠的肝脏中降解基因（PAM、PTGS 1和PTGS 2）的上调， 伴随着显著减少的NAA，如代谢组学所确定的。肝脏NAA呈负相关 NASH和炎症指数。重要的是，长期施用N-油酰亮氨酸（C18：1-Leu），如 概念验证，防止饮食诱导的NASH，不依赖于全身能量代谢的变化。 这与诱导肝脏过氧化物酶体增殖物激活受体α（PPARα）/脂肪酸 氧化（FAO）、抑制C-C基序趋化因子配体2（CCL 2）和减少肝巨噬细胞， 纤维化在动脉粥样硬化小鼠中，C18：1-Leu减少了病变巨噬细胞和动脉粥样硬化， 同时降低肝脂肪变性和CCL 2。因此，我们的研究结果支持了NAAs在 NASH和动脉粥样硬化的同时治疗。这个项目将解决的中心假设，脂质 超负荷和随后的炎症抑制肝脏NAA的形成，而NAA刺激肝脏PPARα和 抑制CCL 2，同时降低NASH和动脉粥样硬化。目标1将确定机制 在NASH和动脉粥样硬化中使用体外和体内模型来驱动抑制NAAs， NAA代谢基因的功能，并将在GWAS中定义这些基因中连接两种疾病的遗传变异 和人类肝脏样本目的2将NAAs定义为NASH的潜在治疗方法，从而治疗动脉粥样硬化， 其对PPARα介导的肝脏FAO的依赖性和使用新的肝脏特异性和饮食抑制CCL 2 小鼠模型与体外方法相结合。这项工作将描述一个新发现的代谢 NASH和动脉粥样硬化之间的联系，并为加速NAAs的发展提供机制数据 作为这些疾病的同时治疗，从而解决了显著未满足的临床需求。