Institute of Physiology, Czech Academy of Sciences, 142 20 Prague 4, Czech Republic.
Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
Proc Natl Acad Sci U S A. 2021 Jan 12;118(2). doi: 10.1073/pnas.2020999118.
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.
支链棕榈酸酯和羟基硬脂酸酯是具有抗炎和抗糖尿病作用的脂肪因子，属于羟脂肪酸（HFAs）的脂肪酸（FA）酯家族，称为 FAHFAs。FAHFAs 本身属于寡聚 FA 酯，称为 estolides。甘油结合的 FAHFAs 在三酰基甘油（TAG）中，称为 TAG estolides，作为脂肪酶按需动员 FAHFAs 的代谢物储库。在这里，我们研究了两种主要代谢脂肪酶，脂肪甘油三酯脂肪酶（ATGL）和激素敏感脂肪酶（HSL），在 TAG estolide 和 FAHFA 降解中的作用。我们合成了 20 种具有不同支化位置、链长、饱和度等级和甘油主链位置的 FAHFAs 的 TAG estolide 异构体文库，并开发了所有预测代谢中间产物的计算质谱文库。我们发现 ATGL 单独或与比较基因鉴定-58 共同激活，可有效地从 TAG estolide 中释放 FAHFAs，优先选择更紧凑的底物，其中 estolide 支化点靠近甘油酯键。ATGL 进一步参与转酯化和重塑反应，导致具有替代酰基组成的 TAG estolide 形成。HSL 是 TAG estolide 和游离 FAHFA 的更强效的 estolide 键水解酶。缺乏 HSL 的白色脂肪组织中 FAHFA 和 TAG estolide 的积累表明 HSL 在体内 estolide 代谢中具有功能作用。我们的数据表明，ATGL 和 HSL 以不同的方式参与 estolide 和 TAG estolide 的代谢，可能会影响 FAHFAs 的脂因子功能。
