Distinct roles of adipose triglyceride lipase and hormone-sensitive lipase in the catabolism of triacylglycerol estolides
Contributed by Rudolf Zechner, November 13, 2020 (sent for review October 7, 2020; reviewed by Robert V. Farese Jr. and Stephen G. Young)
Significance
Fat mass is controlled by the balance of triacylglycerol (TAG) degradation and synthesis. Adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) are key players in TAG catabolism providing fatty acids (FAs) as energy substrates and metabolic intermediates. Here, we show that ATGL and HSL metabolize TAGs containing antidiabetic lipid mediators (FA esters of hydroxy FAs), distinctly controlling the release of bioactive lipids. Our paper connects lipolysis-mediated TAG metabolism with the regulation of antidiabetic signaling lipids.
Abstract
Branched esters of palmitic acid and hydroxy stearic acid are antiinflammatory and antidiabetic lipokines that belong to a family of fatty acid (FA) esters of hydroxy fatty acids (HFAs) called FAHFAs. FAHFAs themselves belong to oligomeric FA esters, known as estolides. Glycerol-bound FAHFAs in triacylglycerols (TAGs), named TAG estolides, serve as metabolite reservoir of FAHFAs mobilized by lipases upon demand. Here, we characterized the involvement of two major metabolic lipases, adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL), in TAG estolide and FAHFA degradation. We synthesized a library of 20 TAG estolide isomers with FAHFAs varying in branching position, chain length, saturation grade, and position on the glycerol backbone and developed an in silico mass spectra library of all predicted catabolic intermediates. We found that ATGL alone or coactivated by comparative gene identification-58 efficiently liberated FAHFAs from TAG estolides with a preference for more compact substrates where the estolide branching point is located near the glycerol ester bond. ATGL was further involved in transesterification and remodeling reactions leading to the formation of TAG estolides with alternative acyl compositions. HSL represented a much more potent estolide bond hydrolase for both TAG estolides and free FAHFAs. FAHFA and TAG estolide accumulation in white adipose tissue of mice lacking HSL argued for a functional role of HSL in estolide catabolism in vivo. Our data show that ATGL and HSL participate in the metabolism of estolides and TAG estolides in distinct manners and are likely to affect the lipokine function of FAHFAs.
Data Availability
All study data are included in the paper and SI Appendix.
Acknowledgments
This work was supported by grants from the Czech Science Foundation (20-00317S) and the Czech Academy of Sciences (LQ200111901; RVO Grant 61388963), projects P 32225-B (to F.P.W.R.) and F7302 SFB LIPID HYDROLYSIS (to R.Z.) funded by the Austrian Funds zur Förderung der Wissenschaftlichen Forschung, the Fondation Leducq Transatlantic Network grant 12CVD04 (R.Z.), the Louis-Jeantet Prize for Medicine 2015 (R.Z.), and the European Research Council (ERC) under the European Union’s Seventh Framework Programme (FP/2007-2013)/ERC Grant Agreement 340896 (R.Z.). We thank Dr. Martin Dracinsky for measuring samples.
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© 2021. Published under the PNAS license.
Data Availability
All study data are included in the paper and SI Appendix.
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Published online: December 28, 2020
Published in issue: January 12, 2021
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Acknowledgments
This work was supported by grants from the Czech Science Foundation (20-00317S) and the Czech Academy of Sciences (LQ200111901; RVO Grant 61388963), projects P 32225-B (to F.P.W.R.) and F7302 SFB LIPID HYDROLYSIS (to R.Z.) funded by the Austrian Funds zur Förderung der Wissenschaftlichen Forschung, the Fondation Leducq Transatlantic Network grant 12CVD04 (R.Z.), the Louis-Jeantet Prize for Medicine 2015 (R.Z.), and the European Research Council (ERC) under the European Union’s Seventh Framework Programme (FP/2007-2013)/ERC Grant Agreement 340896 (R.Z.). We thank Dr. Martin Dracinsky for measuring samples.
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The authors declare no competing interest.
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Distinct roles of adipose triglyceride lipase and hormone-sensitive lipase in the catabolism of triacylglycerol estolides, Proc. Natl. Acad. Sci. U.S.A.
118 (2) e2020999118,
https://doi.org/10.1073/pnas.2020999118
(2021).
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