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  2. Silencing TXNIP ameliorates high uric acid-induced insulin resistance via the IRS2/AKT and Nrf2/HO-1 pathways in macrophages

Silencing TXNIP ameliorates high uric acid-induced insulin resistance via the IRS2/AKT and Nrf2/HO-1 pathways in macrophages

  • Free Radic Biol Med. 2022 Jan;178:42-53. doi: 10.1016/j.freeradbiomed.2021.11.034.
Wei Yu 1 Chunjuan Chen 2 Wanling Zhuang 3 Wei Wang 1 Weidong Liu 1 Hairong Zhao 1 Jiaming Lv 1 De Xie 1 Qiang Wang 1 Furong He 1 Chenxi Xu 1 Bingyang Chen 1 Tetsuya Yamamoto 4 Hidenori Koyama 4 Jidong Cheng 5
Affiliations

Affiliations

  • 1 Department of Internal Medicine, Xiang'an Hospital of Xiamen University, School of Medicine Xiamen University, Xiamen, China.
  • 2 Department of Cardiology, The Second Affiliated Hospital of Shantou University Medical College, Shantou, China.
  • 3 Department of Hematology, The First Affiliated Hospital of Shantou University Medical College, Shantou, China.
  • 4 Department of Diabetes, Endocrinology and Clinical Immunology, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
  • 5 Department of Internal Medicine, Xiang'an Hospital of Xiamen University, School of Medicine Xiamen University, Xiamen, China; Department of Diabetes, Endocrinology and Clinical Immunology, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan; Xiamen Key Laboratory of Translational Medicine for Nucleic Acid Metabolism and Regulation, Xiamen, Fujian, China. Electronic address: jidongcheng36@hotmail.com.
Abstract

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.

Keywords

High uric acid; IRS2/AKT; Insulin resistance; Nrf2/HO-1; TXNIP.

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