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Disruption of the Phosphate Transporter Pit1 in Hepatocytes Improves Glucose Metabolism and Insulin Signaling by Modulating the USP7/IRS1 Interaction

Abstract : 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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https://hal-univ-bourgogne.archives-ouvertes.fr/hal-01413091
Contributor : Lnc - Université de Bourgogne <>
Submitted on : Friday, December 9, 2016 - 12:55:09 PM
Last modification on : Wednesday, August 19, 2020 - 11:17:21 AM

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Anne Forand, Eugénie Koumakis, Alice Rousseau, Yohann Sassier, Clément Journe, et al.. Disruption of the Phosphate Transporter Pit1 in Hepatocytes Improves Glucose Metabolism and Insulin Signaling by Modulating the USP7/IRS1 Interaction. Cell Reports, Elsevier Inc, 2016, 16 (10), pp.2736 - 2748. ⟨10.1016/j.celrep.2016.08.012⟩. ⟨hal-01413091⟩

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