Department of Internal Medicine, Xiang'an Hospital of Xiamen University, School of Medicine Xiamen University, Xiamen, China.
Department of Cardiology, The Second Affiliated Hospital of Shantou University Medical College, Shantou, China.
Free Radic Biol Med. 2022 Jan;178:42-53. doi: 10.1016/j.freeradbiomed.2021.11.034. Epub 2021 Nov 27.
Insulin resistance (IR) promotes atherosclerosis and increases the risk of diabetes and cardiovascular diseases. Our previous studies have demonstrated that high uric acid (HUA) increased oxidative stress, leading to IR in cardiomyocytes and pancreatic β cells. However, whether HUA can induce IR in monocytes/macrophages, which play critical roles in all stages of atherosclerosis, is unclear. Recent findings revealed that thioredoxin-interacting protein (TXNIP) negatively regulates insulin signaling; however, the roles and mechanisms of TXNIP in HUA-induced IR remain unclear. Therefore, in this study, we investigated the function of TXNIP in macrophages treated with UA. Transcriptomic profiling revealed TXNIP as one of the most upregulated genes, and subsequent RT-PCR and Western blot analyses confirmed that TXNIP was upregulated by HUA. HUA treatment significantly increased mitochondrial reactive oxygen species (MtROS) levels and decreased insulin-stimulated glucose uptake. Silencing TXNIP by RNA interference significantly diminished HUA-induced oxidative stress and IR. Mechanistically, silencing TXNIP reversed the inhibition of the phosphorylation of insulin receptor substrate 2 (IRS2)/protein kinase B (AKT) pathway induced by HUA. Additional study revealed that HUA induced the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) signaling pathway, but silencing TXNIP abolished it. Moreover, Nrf2 inhibitor (ML385) ameliorated HUA-induced IR independent of IRS2/AKT signaling. Probenecid, a well-known UA-lowering drug, significantly suppressed the activation of TXNIP and Nrf2/HO-1 signaling. Furthermore, RNA-seq revealed that activation of the TXNIP-related redox pathway may be a key regulator in patients with asymptomatic hyperuricemia. These data suggest that silencing TXNIP could ameliorate HUA-induced IR via the IRS2/AKT and Nrf2/HO-1 pathways in macrophages. Additionally, TXNIP might be a promising therapeutic target for preventing and treating oxidative stress and IR induced by HUA.
胰岛素抵抗（IR）促进动脉粥样硬化，并增加糖尿病和心血管疾病的风险。我们之前的研究表明，高尿酸（HUA）增加氧化应激，导致心肌细胞和胰岛β细胞的 IR。然而，HUA 是否可以诱导在动脉粥样硬化的所有阶段都发挥关键作用的单核细胞/巨噬细胞中的 IR 尚不清楚。最近的研究结果表明，硫氧还蛋白相互作用蛋白（TXNIP）负调节胰岛素信号；然而，TXNIP 在 HUA 诱导的 IR 中的作用和机制尚不清楚。因此，在这项研究中，我们研究了 UA 处理的巨噬细胞中 TXNIP 的功能。转录组谱分析显示 TXNIP 是上调最明显的基因之一，随后的 RT-PCR 和 Western blot 分析证实 HUA 上调了 TXNIP。HUA 处理显著增加了线粒体活性氧（MtROS）水平，并降低了胰岛素刺激的葡萄糖摄取。通过 RNA 干扰沉默 TXNIP 可显著减轻 HUA 诱导的氧化应激和 IR。在机制上，沉默 TXNIP 逆转了 HUA 诱导的胰岛素受体底物 2（IRS2）/蛋白激酶 B（AKT）通路磷酸化的抑制。进一步的研究表明，HUA 诱导了核因子红细胞 2 相关因子 2（Nrf2）/血红素加氧酶 1（HO-1）信号通路的激活，但沉默 TXNIP 则使其失活。此外，Nrf2 抑制剂（ML385）可独立于 IRS2/AKT 信号改善 HUA 诱导的 IR。一种众所周知的降低尿酸药物丙磺舒可显著抑制 TXNIP 和 Nrf2/HO-1 信号的激活。此外，RNA-seq 表明 TXNIP 相关的氧化还原途径的激活可能是无症状高尿酸血症患者的关键调节因子。这些数据表明，沉默 TXNIP 可通过 IRS2/AKT 和 Nrf2/HO-1 通路改善巨噬细胞中 HUA 诱导的 IR。此外，TXNIP 可能是预防和治疗 HUA 诱导的氧化应激和 IR 的有前途的治疗靶点。
