HU-671, a Novel Oleoyl Serine Derivative, Exhibits Enhanced Efficacy in Reversing Ovariectomy-Induced Osteoporosis and Bone Marrow Adiposity

Baraghithy, Saja; Smoum, Reem; Attar-Namdar, Malka; Mechoulam, Raphael; Bab, Itai; Tam, Joseph

doi:10.3390/molecules24203719

Cited by 6 publications

(4 citation statements)

References 70 publications

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“…Pharmacological, genetic, and mechanistic studies in rodents suggest that certain members of the N-acyl amino acids stimulate mitochondrial respiration and whole-body energy expenditure 1 . Other complementary studies have also established roles for N-acyl amino acids in glucose homeostasis 2 , adipogenesis 5 , vascular tone 6, 7 , and bone homeostasis 8, 9 . Importantly, the functional consequence and enzymatic regulation of each N-acyl amino acid is highly dependent on the structural properties of the fatty acid tail group and amino acid head group.…”

Section: Mainmentioning

confidence: 99%

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

Tanzo

Wiggenhorn

et al. 2023

Preprint

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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 genetic regulation of four plasma N-fatty acyl amino acids (N-oleoyl-leucine, N-oleoyl-phenylalanine, N-oleoyl-serine, and N-oleoyl-glycine) in 2,351 individuals from the Jackson Heart Study. N-oleoyl-leucine and N-oleoyl-phenylalanine were positively associated with traits related to energy balance, including body mass index, waist circumference, and subcutaneous adipose tissue. In addition, we identify the CYP4F2 locus as a human-specific genetic determinant of plasma N-oleoyl-leucine and N-oleoyl-phenylalanine levels. In vitro, 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 (FAHFAs). By contrast, FAAH-regulated N-oleoyl-glycine and N-oleoyl-serine were inversely associated with traits related to glucose and lipid homeostasis. These data uncover a human-specific enzymatic node for the metabolism of a subset of N-fatty acyl amino acids and establish a framework for understanding the cardiometabolic roles of individual N-fatty acyl amino acids in humans.

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Section: Mainmentioning

confidence: 99%

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

Tanzo

Wiggenhorn

et al. 2023

Preprint

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“…N -oleoyl-serine (NOleS) is the most studied member of this family of lipids [ 123 ]. Lately, a derivative of NOleS – HU-671 – was shown to reverse ovariectomy-induced osteoporosis and bone marrow adiposity more efficaciously than the endogenous compound [ 124 ]. To date, little is known about the molecular target of NASers.…”

Section: Characteristics and Importance Of Ecbome Mediators From A Nutritional Standpointmentioning

confidence: 99%

(Wh)olistic (E)ndocannabinoidome-Microbiome-Axis Modulation through (N)utrition (WHEN) to Curb Obesity and Related Disorders

Sihag

Marzo

2022

Lipids Health Dis

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The discovery of the endocannabinoidome (eCBome) is evolving gradually with yet to be elucidated functional lipid mediators and receptors. The diet modulates these bioactive lipids and the gut microbiome, both working in an entwined alliance. Mounting evidence suggests that, in different ways and with a certain specialisation, lipid signalling mediators such as N-acylethanolamines (NAEs), 2-monoacylglycerols (2-MAGs), and N-acyl-amino acids (NAAs), along with endocannabinoids (eCBs), can modulate physiological mechanisms underpinning appetite, food intake, macronutrient metabolism, pain sensation, blood pressure, mood, cognition, and immunity. This knowledge has been primarily utilised in pharmacology and medicine to develop many drugs targeting the fine and specific molecular pathways orchestrating eCB and eCBome activity. Conversely, the contribution of dietary NAEs, 2-MAGs and eCBs to the biological functions of these molecules has been little studied. In this review, we discuss the importance of (Wh) olistic (E)ndocannabinoidome-Microbiome-Axis Modulation through (N) utrition (WHEN), in the management of obesity and related disorders.

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“…NAAs are present in tissue , and blood of mammalian . They function as pleiotropic bioactive lipids for nociception, bone function, , metabolism, , and neurodegeneration . Recently, several novel amino acid-conjugated bile acids were reported to agonize the farnesoid X receptor .…”

Section: Introductionmentioning

confidence: 99%

Discovery of N-Acyl Amino Acids and Novel Related N-, O-Acyl Lipids by Integrating Molecular Networking and an Extended In Silico Spectral Library

Yuan

et al. 2023

Anal. Chem.

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Research on novel bioactive lipids has garnered increasing interest. Although lipids can be identified by searching mass spectral libraries, the discovery of novel lipids remains challenging as the query spectra of such lipids are not included in libraries. In this study, we propose a strategy to discover novel carboxylic acid-containing acyl lipids by integrating molecular networking with an extended in silico spectral library. Derivatization was performed to improve the response of this method. The tandem mass spectrometry spectra enriched by derivatization facilitated the formation of molecular networking and 244 nodes were annotated. We constructed consensus spectra for these annotations based on molecular networking and developed an extended in silico spectral library based on these consensus spectra. The spectral library included 6879 in silico molecules covering 12,179 spectra. Using this integration strategy, 653 acyl lipids were discovered. Among these, O-acyl lactic acids and N-lactoyl amino acid-conjugated lipids were annotated as novel acyl lipids. Compared with conventional methods, our proposed method allows for the discovery of novel acyl lipids, and extended in silico libraries significantly increase the size of the spectral library.

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HU-671, a Novel Oleoyl Serine Derivative, Exhibits Enhanced Efficacy in Reversing Ovariectomy-Induced Osteoporosis and Bone Marrow Adiposity

Cited by 6 publications

References 70 publications

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

(Wh)olistic (E)ndocannabinoidome-Microbiome-Axis Modulation through (N)utrition (WHEN) to Curb Obesity and Related Disorders

Discovery of N-Acyl Amino Acids and Novel Related N-, O-Acyl Lipids by Integrating Molecular Networking and an Extended In Silico Spectral Library

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