Division of Nephrology, Department of Medicine, The Research Institute of St. Joe's Hamilton and the Hamilton Centre for Kidney Research, McMaster University, Hamilton, Ontario, Canada.
Department of Pediatrics, School of Medicine, University of Colorado Health Sciences Center, Aurora, Colorado, USA.
J Biol Chem. 2024 Feb;300(2):105655. doi: 10.1016/j.jbc.2024.105655. Epub 2024 Jan 16.
Endoplasmic reticulum stress is associated with insulin resistance and the development of nonalcoholic fatty liver disease. Deficiency of the endoplasmic reticulum stress response T-cell death-associated gene 51 (TDAG51) (TDAG51) in mice promotes the development of high-fat diet (HFD)-induced obesity, fatty liver, and hepatic insulin resistance. However, whether this effect is due specifically to hepatic TDAG51 deficiency is unknown. Here, we report that hepatic TDAG51 protein levels are consistently reduced in multiple mouse models of liver steatosis and injury as well as in liver biopsies from patients with liver disease compared to normal controls. Delivery of a liver-specific adeno-associated virus (AAV) increased hepatic expression of a TDAG51-GFP fusion protein in WT, TDAG51, and leptin-deficient (ob/ob) mice. Restoration of hepatic TDAG51 protein was sufficient to increase insulin sensitivity while reducing body weight and fatty liver in HFD fed TDAG51 mice and in ob/ob mice. TDAG51 mice expressing ectopic TDAG51 display improved Akt (Ser473) phosphorylation, post-insulin stimulation. HFD-fed TDAG51 mice treated with AAV-TDAG51-GFP displayed reduced lipogenic gene expression, increased beta-oxidation and lowered hepatic and serum triglycerides, findings consistent with reduced liver weight. Further, AAV-TDAG51-GFP-treated TDAG51 mice exhibited reduced hepatic precursor and cleaved sterol regulatory-element binding proteins (SREBP-1 and SREBP-2). In vitro studies confirmed the lipid-lowering effect of TDAG51 overexpression in oleic acid-treated Huh7 cells. These studies suggest that maintaining hepatic TDAG51 protein levels represents a viable therapeutic approach for the treatment of obesity and insulin resistance associated with nonalcoholic fatty liver disease.
内质网应激与胰岛素抵抗和非酒精性脂肪性肝病的发展有关。内质网应激反应 T 细胞死亡相关基因 51（TDAG51）（TDAG51）在小鼠中的缺乏促进高脂肪饮食（HFD）诱导的肥胖、脂肪肝和肝胰岛素抵抗的发展。然而，这种效应是否专门归因于肝 TDAG51 缺乏尚不清楚。在这里，我们报告说，与正常对照相比，多种小鼠肝脂肪变性和损伤模型以及肝病患者的肝活检中，肝 TDAG51 蛋白水平持续降低。肝脏特异性腺相关病毒（AAV）的传递增加了 WT、TDAG51 和瘦素缺陷（ob/ob）小鼠中 TDAG51-GFP 融合蛋白的肝表达。肝 TDAG51 蛋白的恢复足以增加胰岛素敏感性，同时降低 HFD 喂养的 TDAG51 小鼠和 ob/ob 小鼠的体重和脂肪肝。表达异位 TDAG51 的 TDAG51 小鼠表现出 Akt（Ser473）磷酸化增加，胰岛素刺激后。用 AAV-TDAG51-GFP 治疗的 HFD 喂养的 TDAG51 小鼠显示出降低的脂肪生成基因表达、增加的β氧化和降低的肝和血清甘油三酯，这些发现与降低的肝重一致。此外，AAV-TDAG51-GFP 治疗的 TDAG51 小鼠表现出降低的肝前体和切割固醇调节元件结合蛋白（SREBP-1 和 SREBP-2）。体外研究证实了 TDAG51 过表达在油酸处理的 Huh7 细胞中的降脂作用。这些研究表明，维持肝 TDAG51 蛋白水平代表了治疗与非酒精性脂肪性肝病相关的肥胖和胰岛素抵抗的可行治疗方法。
