Stereochemistry of Endogenous Palmitic Acid Ester of 9-Hydroxystearic Acid and Relevance of Absolute Configuration to Regulation

J Am Chem Soc. 2017 Apr 5;139(13):4943-4947. doi: 10.1021/jacs.7b01269. Epub 2017 Mar 28.

Abstract

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 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.

Publication types

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

MeSH terms

  • Adipose Tissue / chemistry*
  • Adipose Tissue / metabolism
  • Animals
  • Esters / chemical synthesis
  • Esters / chemistry*
  • Esters / metabolism
  • HEK293 Cells
  • Humans
  • Lipase / metabolism
  • Lipids / chemistry
  • Mice
  • Mice, Transgenic
  • Molecular Structure
  • Palmitic Acid / chemical synthesis
  • Palmitic Acid / chemistry*
  • Palmitic Acid / metabolism
  • Stearic Acids / chemistry*
  • Stearic Acids / metabolism
  • Stereoisomerism

Substances

  • Esters
  • Lipids
  • Stearic Acids
  • Palmitic Acid
  • 9-hydroxystearic acid
  • CEL protein, human
  • Lipase