内分泌学
内科学
胰岛素抵抗
胰岛素
IRS1
脂肪生成
胰岛素受体
2型糖尿病
糖尿病
碳水化合物代谢
葡萄糖稳态
葡萄糖转运蛋白
化学
脂质代谢
生物
医学
作者
Anne Forand,Eugénie Koumakis,Alice Rousseau,Yohann Sassier,Clément Journe,Jean-François Merlin,Christine Leroy,R.H. Khonsari,Patrice Codogno,Gérard Friedlander,Isabelle Cohen
出处
期刊:Cell Reports
[Elsevier]
日期:2016-09-01
卷期号:16 (10): 2736-2748
被引量:31
标识
DOI:10.1016/j.celrep.2016.08.012
摘要
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.
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