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J Am Chem Soc. 2019 Jun 5;141(22):8798-8806. doi: 10.1021/jacs.9b00045. Epub 2019 May 13.

Discovery of FAHFA-Containing Triacylglycerols and Their Metabolic Regulation.

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Clayton Foundation Laboratories for Peptide Biology , Salk Institute for Biological Studies , 10010 North Torrey Pines Road , La Jolla , California 92037-1002 , United States.
Skaggs School of Pharmacy and Pharmaceutical Sciences , University of California-San Diego , 9500 Gilman Drive , La Jolla , California 92093-0934 , United States.
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine , Beth Israel Deaconess Medical Center, Harvard Medical School , Boston , Massachusetts 02215 , United States.


FAHFAs are a class of bioactive lipids, which show great promise for treating diabetes and inflammatory diseases. Deciphering the metabolic pathways that regulate endogenous FAHFA levels is critical for developing diagnostic and therapeutic strategies. However, it remains unclear how FAHFAs are metabolized in cells or tissues. Here, we investigate whether FAHFAs can be incorporated into other lipid classes and identify a novel class of endogenous lipids, FAHFA-containing triacylglycerols (FAHFA-TGs), which contain a FAHFA group esterified to the glycerol backbone. Isotope-labeled FAHFAs are incorporated into FAHFA-TGs when added to differentiated adipocytes, which implies the existence of enzymes and metabolic pathways capable of synthesizing these lipids. Induction of lipolysis (i.e., triacylglycerol hydrolysis) in adipocytes is associated with marked increases in nonesterified FAHFA levels, demonstrating that FAHFA-TGs breakdown is a regulator of cellular FAHFA levels. To quantify FAHFA levels in FAHFA-TGs and determine their regioisomeric distributions, we developed a mild alkaline hydrolysis method that liberates FAHFAs from triacylglycerols for easier detection. FAHFA-TG concentrations are greater than 100-fold than that of nonesterified FAHFAs, indicating that FAHFA-TGs are a major reservoir of FAHFAs in cells and tissues. The discovery of FAHFA-TGs reveals a new branch of TG and FAHFA metabolism with potential roles in metabolic health and regulation of inflammation.

[Available on 2020-06-05]

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