Transcription profiling by array of liver tissues from mice with liver-specific knockout of Pit1 and wild-type littermates fed with either a high-fat diet or chow control diet

The liver plays a central role in whole-body lipid and glucose homeostasis. Increasing dietary fat intake results in increased hepatic fat deposition, which is associated with a risk for development of insulin resistance and type 2 diabetes. In this study, we demonstrate a role for the phosphate inorganic transporter 1 (PiT1/SLC20A1) in regulating metabolism. Specific knockout of Pit1 in hepatocytes significantly improved glucose tolerance and insulin sensitivity, enhanced insulin signalling, and decreased hepatic lipogenesis. We identified USP7 as a PiT1 binding partner and demonstrated that Pit1 deletion inhibited USP7/IRS1 dissociation upon insulin stimulation. This prevented IRS1 ubiquitination and its subsequent proteasomal degradation. As a consequence delayed insulin negative feedback loop and sustained insulin signalling were observed. Moreover, PiT1-deficient mice were protected against high fat diet-induced obesity and diabetes. Our findings indicate that PiT1 has potential as a therapeutic target in the context of metabolic syndrome, obesity, and diabetes.肝脏在全身脂质与葡萄糖稳态中发挥核心调控作用。膳食脂肪摄入增加可导致肝脏脂肪沉积增多，该过程与胰岛素抵抗及2型糖尿病的发病风险密切相关。本研究揭示了无机磷酸盐转运蛋白1（phosphate inorganic transporter 1, PiT1/SLC20A1）在代谢调控中的功能。肝细胞中特异性敲除Pit1可显著改善葡萄糖耐量与胰岛素敏感性，增强胰岛素信号通路活性，并降低肝脏脂肪生成水平。研究团队鉴定出泛素特异性蛋白酶7（USP7）为PiT1的结合伴侣，并证实胰岛素刺激下Pit1缺失会抑制USP7与胰岛素受体底物1（IRS1）的解离，从而阻断IRS1的泛素化及其后续的蛋白酶体降解过程。由此可延缓胰岛素负反馈环路，维持持续的胰岛素信号传导。此外，PiT1缺陷小鼠可抵抗高脂饮食诱导的肥胖与糖尿病。本研究结果表明，PiT1有望成为代谢综合征、肥胖及糖尿病的潜在治疗靶点。