Distinct biological activities of isomers from several families of branched fatty acid esters of hydroxy fatty acids (FAHFAs).
Distinct biological activities of isomers from several families of branched fatty acid esters of hydroxy fatty acids (FAHFAs).
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DOI：
10.1016/j.jlr.2021.100108
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发表时间：
2021
影响因子：
6.5
通讯作者：
Kahn BB
中科院分区：
文献类型：
--
作者：
Aryal P;Syed I;Lee J;Patel R;Nelson AT;Siegel D;Saghatelian A;Kahn BB
羟基脂肪酸的支链脂肪酸酯(FAHFAs)是一种具有抗糖尿病和抗炎作用的内源性脂类。每个FAHFA家族由具有不同酰基链的酯和具有不同碳分支点的多个异构体组成。一些FAHFA，包括棕榈酸羟基硬脂酸(PAHSA)，通过促进葡萄糖刺激的胰岛素分泌(GSIS)、胰岛素刺激的葡萄糖转运和胰岛素抑制肝脏葡萄糖产生和减轻脂肪组织炎症的作用来改善小鼠的胰岛素敏感性和葡萄糖耐量。然而，人们对其他FAHFA的生物学效应知之甚少。在这里，我们研究了PAHSA、油酸、羟基硬脂酸、棕榈油酸羟基硬脂酸和硬脂酸羟基硬脂酸是否增强了β-细胞和人类胰岛的GSI，胰岛素刺激的脂肪细胞的葡萄糖摄取，以及免疫细胞的抗炎作用。我们还研究了它们是否激活了G蛋白偶联受体40，后者介导了PAHSA在体内对胰岛素分泌和敏感性的影响。我们发现许多FAHFA增强GSIS，激活G蛋白偶联受体40，并减弱内毒素诱导的免疫细胞中趋化因子和细胞因子的表达、分泌和吞噬。然而，较少的FAHFA增加了脂肪细胞对胰岛素刺激的葡萄糖摄取。S-9-PAHSA可增强GSI和葡萄糖摄取，而R-9-PAHSA无此作用，而两种立体异构体均有抗炎作用。含有高支化度的不饱和酰基的脂肪酸更有可能增强GSIS，而低支化度的脂肪酸更有可能抗炎。这项研究揭示了不同FAHFAs生物学作用的特异性，并可能导致FAHFAs用于治疗代谢和免疫介导性疾病。
Branched fatty acid esters of hydroxy fatty acids (FAHFAs) are endogenous lipids with antidiabetic and anti-inflammatory effects. Each FAHFA family consists of esters with different acyl chains and multiple isomers with branch points at different carbons. Some FAHFAs, including palmitic acid hydroxy stearic acids (PAHSAs), improve insulin sensitivity and glucose tolerance in mice by enhancing glucose-stimulated insulin secretion (GSIS), insulin-stimulated glucose transport, and insulin action to suppress hepatic glucose production and reducing adipose tissue inflammation. However, little is known about the biological effects of other FAHFAs. Here, we investigated whether PAHSAs, oleic acid hydroxy stearic acid, palmitoleic acid hydroxy stearic acid, and stearic acid hydroxy stearic acid potentiate GSIS in β-cells and human islets, insulin-stimulated glucose uptake in adipocytes, and anti-inflammatory effects in immune cells. We also investigated whether they activate G protein–coupled receptor 40, which mediates the effects of PAHSAs on insulin secretion and sensitivity in vivo. We show that many FAHFAs potentiate GSIS, activate G protein–coupled receptor 40, and attenuate LPS-induced chemokine and cytokine expression and secretion and phagocytosis in immune cells. However, fewer FAHFAs augment insulin-stimulated glucose uptake in adipocytes. S-9-PAHSA, but not R-9-PAHSA, potentiated GSIS and glucose uptake, while both stereoisomers had anti-inflammatory effects. FAHFAs containing unsaturated acyl chains with higher branching from the carboxylate head group are more likely to potentiate GSIS, whereas FAHFAs with lower branching are more likely to be anti-inflammatory. This study provides insight into the specificity of the biological actions of different FAHFAs and could lead to the development of FAHFAs to treat metabolic and immune-mediated diseases.