Department of Pharmacology, New York Medical College School of Medicine, Valhalla, NY, United States.
Department of Biochemistry, University of Texas Southwestern Medical Center, TX, United States.
Prostaglandins Other Lipid Mediat. 2021 Feb;152:106485. doi: 10.1016/j.prostaglandins.2020.106485. Epub 2020 Oct 1.
20-HETE, a metabolite of arachidonic acid produced by Cytochrome P450 (CYP) 4A/4 F, has been implicated in the development of obesity-associated complications such as diabetes and insulin resistance. In this study, we examined whether the acute elevation of 20-HETE levels contributes to the development of diet-driven hyperglycemia and insulin resistance. We employed a conditional transgenic mouse model to overexpress Cyp4a12 (Cyp4a12tg), a murine 20-HETE synthase, together with high fat diet (HFD) feeding. Mice in which Cyp4a12 was induced by doxycycline (DOX) at the onset of HFD feeding gained weight at a greater rate and extent than corresponding DOX-untreated Cyp4a12 mice. Cyp4a12tg mice fed HFD + DOX displayed hyperglycemia and impaired glucose metabolism while corresponding HFD-fed Cyp4a12tg mice (no DOX) did not. Importantly, administration of a 20-HETE antagonist, 20-SOLA, to Cyp4a12tg mice fed HFD + DOX significantly attenuated weight gain and prevented the development of hyperglycemia and impaired glucose metabolism. Levels of insulin receptor (IR) phosphorylation at Tyrosine 972 and insulin receptor substrate-1 (IRS1) phosphorylation at serine 307 were markedly decreased and increased, respectively, in liver, skeletal muscle and adipose tissues from Cyp4a12tg mice fed HFD + DOX; 20-SOLA prevented the IR and IRS1 inactivation, suggesting that 20-HETE interferes with insulin signaling. Additional studies in 3T3-1 differentiated adipocytes confirmed that 20-HETE impairs insulin signaling and that its effect may require activation of its receptor GPR75. Taken together, these results provide strong evidence that 20-HETE interferes with insulin function and contributed to diet-driven insulin resistance.
20-HETE，一种花生四烯酸的代谢产物，由细胞色素 P450（CYP）4A/4F 产生，与肥胖相关并发症的发展有关，如糖尿病和胰岛素抵抗。在这项研究中，我们研究了 20-HETE 水平的急性升高是否有助于发展饮食引起的高血糖和胰岛素抵抗。我们使用条件性转基因小鼠模型过度表达 Cyp4a12（Cyp4a12tg），一种鼠类 20-HETE 合酶，同时进行高脂肪饮食（HFD）喂养。在 HFD 喂养开始时用强力霉素（DOX）诱导 Cyp4a12 的小鼠体重增加的速度和幅度都大于未用 DOX 处理的 Cyp4a12 小鼠。喂食 HFD + DOX 的 Cyp4a12tg 小鼠出现高血糖和葡萄糖代谢受损，而相应的 HFD 喂养的 Cyp4a12tg 小鼠（无 DOX）则没有。重要的是，给喂食 HFD + DOX 的 Cyp4a12tg 小鼠施用 20-HETE 拮抗剂 20-SOLA 可显著减轻体重增加并防止高血糖和葡萄糖代谢受损的发展。喂食 HFD + DOX 的 Cyp4a12tg 小鼠的肝、骨骼肌和脂肪组织中胰岛素受体（IR）酪氨酸 972 磷酸化和胰岛素受体底物 1（IRS1）丝氨酸 307 磷酸化水平明显降低和增加，20-SOLA 可防止 IR 和 IRS1 失活，表明 20-HETE 干扰胰岛素信号。在 3T3-1 分化的脂肪细胞中的进一步研究证实，20-HETE 损害胰岛素信号，其作用可能需要其受体 GPR75 的激活。总之，这些结果提供了强有力的证据表明 20-HETE 干扰胰岛素功能并导致饮食引起的胰岛素抵抗。
