CYP4F2 is a human-specific determinant of circulating N-acyl amino acid levels

Julia T Tanzo; Veronica L Li; Amanda L Wiggenhorn; Maria Dolores Moya-Garzon; Wei Wei; Xuchao Lyu; Wentao Dong; Usman A Tahir; Zsu-Zsu Chen; Daniel E Cruz; Shuliang Deng; Xu Shi; Shuning Zheng; Yan Guo; Mario Sims; Monther Abu-Remaileh; James G Wilson; Robert E Gerszten; Jonathan Z Long; Mark D Benson

doi:10.1016/j.jbc.2023.104764

CYP4F2 is a human-specific determinant of circulating N-acyl amino acid levels

J Biol Chem. 2023 Jun;299(6):104764. doi: 10.1016/j.jbc.2023.104764. Epub 2023 Apr 28.

Authors

Julia T Tanzo¹, Veronica L Li², Amanda L Wiggenhorn³, Maria Dolores Moya-Garzon⁴, Wei Wei⁵, Xuchao Lyu⁶, Wentao Dong⁷, Usman A Tahir⁸, Zsu-Zsu Chen⁸, Daniel E Cruz⁸, Shuliang Deng⁸, Xu Shi⁸, Shuning Zheng⁸, Yan Guo⁹, Mario Sims⁹, Monther Abu-Remaileh⁷, James G Wilson⁸, Robert E Gerszten¹⁰, Jonathan Z Long¹¹, Mark D Benson¹²

Affiliations

¹ 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.
² 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, USA.
³ 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.
⁴ Department of Pathology, Stanford University School of Medicine, Stanford, California, USA; Stanford ChEM-H, Stanford University, Stanford, California, USA.
⁵ 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.
⁶ 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.
⁷ Stanford ChEM-H, Stanford University, Stanford, California, USA; Department of Chemical Engineering, Stanford University, Stanford, California, USA.
⁸ Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
⁹ Univ of Mississippi Medical Center, Jackson, Mississippi, USA.
¹⁰ Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA; Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
¹¹ 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, California, USA. Electronic address: jzlong@stanford.edu.
¹² Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. Electronic address: mbenson@bidmc.harvard.edu.

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.

Keywords: CYP4F2; N-acyl amino acid; fatty acid; fatty acid hydroxy fatty acids; functional genomics; metabolomics.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Amino Acids* / blood
Amino Acids* / chemistry
Cardiovascular Diseases
Cytochrome P450 Family 4* / metabolism
Fatty Acids / metabolism
Humans
Leucine
Oleic Acids* / blood
Phenylalanine

Substances

Amino Acids
CYP4F2 protein, human
Cytochrome P450 Family 4
Fatty Acids
Leucine
Phenylalanine
N-oleoylglycine
Oleic Acids

Abstract

Publication types

MeSH terms

Substances

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