Disruption of the Phosphate Transporter Pit1 in Hepatocytes Improves Glucose Metabolism and Insulin Signaling by Modulating the USP7/IRS1 Interaction
Disruption of the Phosphate Transporter Pit1 in Hepatocytes Improves Glucose Metabolism and Insulin Signaling by Modulating the USP7/IRS1 Interaction
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DOI：
10.1016/j.celrep.2016.08.012
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发表时间：
2016-09-06
期刊：
影响因子：
8.8
通讯作者：
Cohen, Isabelle
中科院分区：
文献类型：
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作者：
Forand, Anne;Koumakis, Eugenie;Cohen, Isabelle
肝脏在全身脂质和葡萄糖稳态中起着核心作用。饮食中脂肪摄入量的增加会导致肝脏脂肪沉积的增加，这与胰岛素抵抗和2型糖尿病的发生风险有关。在这项研究中，我们证明了磷酸盐无机转运蛋白1 （PiT1/SLC20A1）在调节代谢中的作用。在肝细胞中特异性敲除Pit1可显著改善葡萄糖耐量和胰岛素敏感性，增强胰岛素信号，减少肝脏脂肪生成。我们确定了USP7是PiT1的结合伙伴，并证明了PiT1的缺失抑制了胰岛素刺激下USP7/IRS1的解离。这阻止了IRS1泛素化及其随后的蛋白酶体降解。结果，观察到延迟的胰岛素负反馈回路和持续的胰岛素信号。此外，pit1缺陷小鼠可以免受高脂肪饮食引起的肥胖和糖尿病的侵害。我们的研究结果表明，PiT1有潜力作为代谢综合征、肥胖和糖尿病的治疗靶点。
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 signaling, 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 signaling 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.