CYP4F2 is a human-specific determinant of circulating N-acyl amino acid levels.
CYP4F2 is a human-specific determinant of circulating N-acyl amino acid levels.
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DOI：
10.1016/j.jbc.2023.104764
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发表时间：
2023-06
影响因子：
4.8
通讯作者：
Benson, Mark D.
中科院分区：
文献类型：
--
作者：
Tanzo, Julia T.;Li, Veronica L.;Wiggenhorn, Amanda L.;Moya-Garzon, Maria Dolores;Wei, Wei;Lyu, Xuchao;Dong, Wentao;Tahir, Usman A.;Chen, Zsu-Zsu;Cruz, Daniel E.;Deng, Shuliang;Shi, Xu;Zheng, Shuning;Guo, Yan;Sims, Mario;Abu-Remaileh, Monther;Wilson, James G.;Gerszten, Robert E.;Long, Jonathan Z.;Benson, Mark D.
N-酰基氨基酸是一大类循环脂质代谢物，可调节啮齿动物的能量消耗和脂肪量。然而，人们对 N-酰基氨基酸在人体中的调节和潜在心脏代谢功能知之甚少。在这里，我们分析了杰克逊心脏研究中 2351 名个体的四种血浆 N-酰基氨基酸（N-油酰-亮氨酸、N-油酰-苯丙氨酸、N-油酰-丝氨酸和 N-油酰-甘氨酸）的心脏代谢表型关联和基因组关联。我们发现，特定 N-酰基氨基酸的血浆水平与心脏代谢疾病终点相关，与游离氨基酸血浆水平无关，并且其模式取决于氨基酸头基。通过将全基因组测序数据与 N-酰基氨基酸水平整合，我们发现 N-酰基氨基酸水平的遗传决定因素也根据氨基酸头基进行聚类。此外，我们确定 CYP4F2 基因座是人血浆中 N-油酰亮氨酸和 N-油酰苯丙氨酸水平的遗传决定因素。在实验研究中，我们证明CYP4F2介导的N-油酰-亮氨酸和N-油酰-苯丙氨酸的羟基化导致代谢多样化并产生许多以前未知的脂质代谢物，这些代谢物具有不同的脂肪酸尾基特征，包括结构上类似于脂肪酸羟基脂肪酸的几种。这些研究为理解人类 N-酰基氨基酸的调节和疾病关联提供了一个结构框架，并确定该脂质信号传导家族的多样性可以通过 CYP4F 介导的 ω-羟基化显着扩展。
N-acyl amino acids are a large family of circulating lipid metabolites that modulate energy expenditure and fat mass in rodents. However, little is known about the regulation and potential cardiometabolic functions of N-acyl amino acids in humans. Here, we analyze the cardiometabolic phenotype associations and genomic associations of four plasma N-acyl amino acids (N-oleoyl-leucine, N-oleoyl-phenylalanine, N-oleoyl-serine, and N-oleoyl-glycine) in 2351 individuals from the Jackson Heart Study. We find that plasma levels of specific N-acyl amino acids are associated with cardiometabolic disease endpoints independent of free amino acid plasma levels and in patterns according to the amino acid head group. By integrating whole genome sequencing data with N-acyl amino acid levels, we identify that the genetic determinants of N-acyl amino acid levels also cluster according to the amino acid head group. Furthermore, we identify the CYP4F2 locus as a genetic determinant of plasma N-oleoyl-leucine and N-oleoyl-phenylalanine levels in human plasma. In experimental studies, we demonstrate that CYP4F2-mediated hydroxylation of N-oleoyl-leucine and N-oleoyl-phenylalanine results in metabolic diversification and production of many previously unknown lipid metabolites with varying characteristics of the fatty acid tail group, including several that structurally resemble fatty acid hydroxy fatty acids. These studies provide a structural framework for understanding the regulation and disease associations of N-acyl amino acids in humans and identify that the diversity of this lipid signaling family can be significantly expanded through CYP4F-mediated ω-hydroxylation.
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影响因子：
3.5
作者：
McGurk KA;Williams SG;Guo H;Watkins H;Farrall M;Cordell HJ;Nicolaou A;Keavney BD
通讯作者：
Keavney BD
影响因子：
7.7
作者：
Floegel A;Stefan N;Yu Z;Mühlenbruch K;Drogan D;Joost HG;Fritsche A;Häring HU;Hrabě de Angelis M;Peters A;Roden M;Prehn C;Wang-Sattler R;Illig T;Schulze MB;Adamski J;Boeing H;Pischon T
通讯作者：
Pischon T
影响因子：
3.7
作者：
Athinarayanan S;Wei R;Zhang M;Bai S;Traber MG;Yates K;Cummings OW;Molleston J;Liu W;Chalasani N
通讯作者：
Chalasani N
影响因子：
2.1
作者：
Conomos MP;Miller MB;Thornton TA
通讯作者：
Thornton TA
影响因子：
14.9
作者：
Buniello, Annalisa;MacArthur, Jacqueline A. L.;Parkinson, Helen
通讯作者：
Parkinson, Helen