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CYP4F2 is a human-specific determinant of circulating N-acyl amino acid levels.
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.
Afiliação
  • Tanzo JT; Department of Pathology, Stanford University School of Medicine, Stanford, California, USA; Stanford ChEM-H, Stanford University, Stanford, California, USA; Stanford Diabetes Research Center, Stanford University, Stanford, California, USA.
  • Li VL; Department of Pathology, Stanford University School of Medicine, Stanford, California, USA; Stanford ChEM-H, Stanford University, Stanford, California, USA; Department of Chemistry, Stanford University, Stanford, California, USA; Wu Tsai Human Performance Alliance, Stanford University, California, U
  • Wiggenhorn AL; Department of Pathology, Stanford University School of Medicine, Stanford, California, USA; Stanford ChEM-H, Stanford University, Stanford, California, USA; Department of Chemistry, Stanford University, Stanford, California, USA.
  • Moya-Garzon MD; Department of Pathology, Stanford University School of Medicine, Stanford, California, USA; Stanford ChEM-H, Stanford University, Stanford, California, USA.
  • Wei W; Department of Pathology, Stanford University School of Medicine, Stanford, California, USA; Stanford ChEM-H, Stanford University, Stanford, California, USA; Department of Biology, Stanford University, Stanford, California, USA.
  • Lyu X; Department of Pathology, Stanford University School of Medicine, Stanford, California, USA; Stanford ChEM-H, Stanford University, Stanford, California, USA; Wu Tsai Human Performance Alliance, Stanford University, California, USA.
  • Dong W; Stanford ChEM-H, Stanford University, Stanford, California, USA; Department of Chemical Engineering, Stanford University, Stanford, California, USA.
  • Tahir UA; Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
  • Chen ZZ; Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
  • Cruz DE; Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
  • Deng S; Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
  • Shi X; Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
  • Zheng S; Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
  • Guo Y; Univ of Mississippi Medical Center, Jackson, Mississippi, USA.
  • Sims M; Univ of Mississippi Medical Center, Jackson, Mississippi, USA.
  • Abu-Remaileh M; Stanford ChEM-H, Stanford University, Stanford, California, USA; Department of Chemical Engineering, Stanford University, Stanford, California, USA.
  • Wilson JG; Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
  • Gerszten RE; Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA; Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
  • Long JZ; Department of Pathology, Stanford University School of Medicine, Stanford, California, USA; Stanford ChEM-H, Stanford University, Stanford, California, USA; Stanford Diabetes Research Center, Stanford University, Stanford, California, USA; Wu Tsai Human Performance Alliance, Stanford University, Cal
  • Benson MD; Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. Electronic address: mbenson@bidmc.harvard.edu.
J Biol Chem ; 299(6): 104764, 2023 06.
Article em En | MEDLINE | ID: mdl-37121548
ABSTRACT
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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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Ácidos Oleicos / Família 4 do Citocromo P450 / Aminoácidos Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: J Biol Chem Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Ácidos Oleicos / Família 4 do Citocromo P450 / Aminoácidos Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: J Biol Chem Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Estados Unidos