Lipidated Amino Acids in Cardiometabolic Diseases
心血管代谢疾病中的脂化氨基酸
基本信息
- 批准号:10503007
- 负责人:
- 金额:$ 32.69万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AcidsAddressAdvanced DevelopmentAffectAmidesAmino AcidsArterial Fatty StreakAtherosclerosisAttentionAutomobile DrivingBiological AssayCardiometabolic DiseaseCardiovascular DiseasesCardiovascular systemCause of DeathChronicClinicalDataDependenceDevelopmentDietDiseaseDyslipidemiasEnergy MetabolismEnzymesFatty AcidsFatty LiverFatty acid glycerol estersFibrosisGenesGeneticGenetic TranscriptionHealthcare SystemsHepaticHepatocyteHistologicHumanIn VitroIndividualInflammationInflammatoryInterventionLesionLeucineLigandsLightLinkLipidsLiverLiver FibrosisLobularLuciferasesMediatingMetabolicMetabolic PathwayModelingMouse StrainsMusNon-Insulin-Dependent Diabetes MellitusObesityPPAR alphaPTGS1 genePTGS2 genePathway interactionsPatientsPharmacologyPopulationRegulationRiskRisk FactorsRoleSamplingSignal PathwaySignaling MoleculeTestingTissuesUp-RegulationVariantWeight GainWorkamino acid metabolismbasecardiometabolic riskchemokinechronic liver diseasedietarydrug candidatedrug developmentfatty acid oxidationgain of functiongenetic variantgenome wide association studygenome-widehepatocyte injuryin vivoin vivo Modelindexinglipid metabolismlong chain fatty acidmacrophagemetabolomicsmonocytemortalitymouse modelnon-alcoholic fatty liver diseasenonalcoholic steatohepatitisnovelnovel therapeutic interventionnovel therapeuticsoverexpressionrecruittranscriptomics
项目摘要
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.
项目概要/摘要
非酒精性脂肪肝病 (NAFLD) 影响着全球 25% 的人口,给人类带来了沉重负担
尽管我们对根本原因的理解取得了重大进展并且相当大。
在药物开发方面,目前尚无针对这种疾病的加速疗法。
与传统危险因素无关的动脉粥样硬化是 NAFLD 患者死亡的主要原因,
特别是对于那些患有更严重的非酒精性脂肪性肝炎(NASH)的患者,因此,临床上存在一个紧迫的问题。
需要确定同时针对 NASH 和动脉粥样硬化的新途径。
代谢和氨基酸代谢失调正在成为 NASH 和
动脉粥样硬化,尽管它们的串扰尚未受到太多关注。
酸(NAA)已成为内源性信号分子,其中酰胺键将氨基酸连接到
然而,人们对 NAA 的代谢调节知之甚少,特别是对于长链脂肪酸的酰基部分。
我们的初步数据表明,肝脏是 NAA 代谢的主要枢纽。
无偏转录组学揭示已知 NAA 生物合成基因(GLYAT、ADH7 和 PM20D1)的抑制
以及患有 NASH 的人和小鼠肝脏中降解基因(PAM、PTGS1 和 PTGS2)的上调,
伴随着 NAA 的显着减少,经代谢组学测定,肝脏 NAA 呈负相关。
重要的是,长期服用 N-油酰亮氨酸 (C18:1-Leu),如
概念验证,防止饮食引起的 NASH,独立于全身能量代谢的变化。
这与肝过氧化物酶体增殖物激活受体 α (PPARα)/脂肪酸的诱导有关
氧化 (FAO)、抑制 C-C 基序趋化因子配体 2 (CCL2) 和减少肝巨噬细胞和
在动脉粥样硬化小鼠中,C18:1-Leu 减少病变巨噬细胞和动脉粥样硬化。
同时降低肝脂肪变性和 CCL2,因此,我们的研究结果支持 NAA 的潜力。
同时治疗 NASH 和动脉粥样硬化 该项目将解决脂质这一中心假设。
超负荷和随之而来的炎症抑制肝脏 NAA 的形成,而 NAA 则刺激肝脏 PPARα 和
抑制 CCL2,同时减少 NASH 和动脉粥样硬化,目标 1 将确定其机制。
使用体外和体内损失和增益模型驱动 NAA 在 NASH 和动脉粥样硬化中的抑制
NAA 代谢基因的功能,并将在 GWAS 中定义这些基因中与两种疾病相关的遗传变异
目标 2 将 NAA 定义为 NASH、动脉粥样硬化和的潜在疗法。
其对 PPARα 介导的肝脏FAO的依赖以及使用新的肝脏特异性和饮食抑制CCL2
这项工作将结合体外方法的小鼠模型来表征新发现的代谢。
连接 NASH 和动脉粥样硬化的途径,并提供机制数据以加速 NAA 的开发
作为这些疾病的同时治疗,从而解决了未满足的重大临床需求。
项目成果
期刊论文数量(0)
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会议论文数量(0)
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Oren Shalom Rom其他文献
Oren Shalom Rom的其他文献
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{{ truncateString('Oren Shalom Rom', 18)}}的其他基金
Dysregulated Oxalate Metabolism in Cardiometabolic Diseases
心脏代谢疾病中草酸代谢失调
- 批准号:
10717214 - 财政年份:2023
- 资助金额:
$ 32.69万 - 项目类别:
Lipidated Amino Acids in Cardiometabolic Diseases
心血管代谢疾病中的脂化氨基酸
- 批准号:
10633254 - 财政年份:2022
- 资助金额:
$ 32.69万 - 项目类别:
Mechanisms of glycine-based therapy for atherosclerosis
甘氨酸治疗动脉粥样硬化的机制
- 批准号:
10381784 - 财政年份:2021
- 资助金额:
$ 32.69万 - 项目类别:
Mechanisms of glycine-based therapy for atherosclerosis
甘氨酸治疗动脉粥样硬化的机制
- 批准号:
10445072 - 财政年份:2021
- 资助金额:
$ 32.69万 - 项目类别:
Mechanisms of glycine-based therapy for atherosclerosis
甘氨酸治疗动脉粥样硬化的机制
- 批准号:
10649691 - 财政年份:2021
- 资助金额:
$ 32.69万 - 项目类别:
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