Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 139, Issue 13, Pages 4943-4947Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jacs.7b01269
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Funding
- National Institutes of Health [R01 DK043051, P30DK57521, R01 DK106210]
- JPB Foundation
- Leona M. and Harry B. Helmsley Charitable Trust [2012-PG-MED002, F30 DK112622, F30 DK112604]
- NCI Cancer Center [CA014195 MASS]
- Dr. Frederick Paulsen Chair/Ferring Pharmaceuticals
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Lipids have fundamental roles in the structure, energetics, and signaling of cells and organisms. The recent discovery of fatty acid esters of hydroxy fatty acids (FAHFAs), lipids with potent antidiabetic and anti-inflammatory activities, indicates that our understanding of the composition of lipidome and the function of lipids is incomplete. The ability to synthesize and test FAHFAs was critical in elucidating the roles 3 of these lipids, but these studies were performed with racemic mixtures, and the role of stereochemistry remains unexplored. Here, we synthesized the R- and S- palmitic acid ester of 9-hydroxystearic acid (R-9-PAHSA, S-9-PAHSA). Access to highly enantioenriched PAHSAs enabled the development of a liquid chromatography mass spectrometry (LC MS) method to separate and quantify R. and S-9-PAHSA, and this approach identified R-9-PAHSA as the predominant stereoisomer that accumulates in adipose tissues from transgenic mice where FAHFAs were first discovered. Furthermore, biochemical analysis of 9-PAHSA biosynthesis and degradation indicate that the enzymes and pathways for PAHSA production are stereospecific, with cell lines favoring the production of R-9-PAHSA and carboxyl ester lipase (CEL), a PAHSA degradative enzyme, selectively hydrolyzing S-9-PAHSA. These studies highlight the role of stereochemistry in the production and degradation of PAHSAs and define the endogenous stereochemistry of 9-PAHSA in adipose tissue. This information will be useful in the identification and characterization of the pathway responsible for PAHSA biosynthesis, and access to enantiopure PAHSAs will elucidate the role of stereochemistry in PAHSA activity and metabolism in vivo.
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