title: 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.
authors: INSERM U1151-CNRS UMR8253, Institut Necker-Enfants Malades (INEM), Paris Descartes University, 75993 Paris, France; Inovarion, 75013 Paris, France. Electronic address: anne.forand@inovarion.com.
authors: Anne
authors: A
authors: Forand
authors: INSERM U1151-CNRS UMR8253, Institut Necker-Enfants Malades (INEM), Paris Descartes University, 75993 Paris, France; Rheumatology Department A, Cochin Hospital, APHP, 75014 Paris, France.
authors: Eugénie
authors: E
authors: Koumakis
authors: INSERM U1151-CNRS UMR8253, Institut Necker-Enfants Malades (INEM), Paris Descartes University, 75993 Paris, France.
authors: Alice
authors: A
authors: Rousseau
authors: INSERM U1151-CNRS UMR8253, Institut Necker-Enfants Malades (INEM), Paris Descartes University, 75993 Paris, France.
authors: Yohann
authors: Y
authors: Sassier
authors: INSERM U1148/FRIM-Paris 7 University, Xavier Bichat Hospital, 75018 Paris, France.
authors: Clément
authors: C
authors: Journe
authors: INSERM U866 NUTox, Plateau Technique de Phénotypage Métabolique et Comportemental du Petit Animal, Agrosup Dijon, 21000 Dijon, France.
authors: Jean-François
authors: JF
authors: Merlin
authors: INSERM U1151-CNRS UMR8253, Institut Necker-Enfants Malades (INEM), Paris Descartes University, 75993 Paris, France.
authors: Christine
authors: C
authors: Leroy
authors: INSERM U1151-CNRS UMR8253, Institut Necker-Enfants Malades (INEM), Paris Descartes University, 75993 Paris, France.
authors: Valérie
authors: V
authors: Boitez
authors: INSERM U1151-CNRS UMR8253, Institut Necker-Enfants Malades (INEM), Paris Descartes University, 75993 Paris, France.
authors: Patrice
authors: P
authors: Codogno
authors: INSERM U1151-CNRS UMR8253, Institut Necker-Enfants Malades (INEM), Paris Descartes University, 75993 Paris, France.
authors: Gérard
authors: G
authors: Friedlander
authors: INSERM U1151-CNRS UMR8253, Institut Necker-Enfants Malades (INEM), Paris Descartes University, 75993 Paris, France.
authors: Isabelle
authors: I
authors: Cohen
mesh_terms: D000273:Adipose Tissue / Q000473:pathology; D000375:Aging / Q000473:pathology; D000818:Animals; D059305:Diet, High-Fat; D005234:Fatty Liver / Q000150:complications / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism; D005943:Gluconeogenesis; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D022781:Hepatocytes / Q000378:metabolism*; D007249:Inflammation / Q000150:complications / Q000473:pathology; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D007333:Insulin Resistance; D018345:Mice, Knockout; D009765:Obesity / Q000473:pathology; D009928:Organ Specificity; D010641:Phenotype; D010766:Phosphorylation; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction; D050817:Transcription Factor Pit-1 / Q000378:metabolism*; D000076084:Ubiquitin-Specific Peptidase 7 / Q000378:metabolism*; D054875:Ubiquitination; D015430:Weight Gain
chemical_list: D005947:Glucose; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D051057:Proto-Oncogene Proteins c-akt; D011972:Receptor, Insulin; D050817:Transcription Factor Pit-1; D000076084:Ubiquitin-Specific Peptidase 7; C526295:Irs1 protein, mouse; C494185:Pou1f1 protein, mouse; C579190:Usp7 protein, mouse