title: Novel Grb14-Mediated Cross Talk between Insulin and p62/Nrf2 Pathways Regulates Liver Lipogenesis and Selective Insulin Resistance.
abstract: A long-standing paradox in the pathophysiology of metabolic diseases is the selective insulin resistance of the liver. It is characterized by a blunted action of insulin to reduce glucose production, contributing to hyperglycemia, while de novo lipogenesis remains insulin sensitive, participating in turn to hepatic steatosis onset. The underlying molecular bases of this conundrum are not yet fully understood. Here, we established a model of selective insulin resistance in mice by silencing an inhibitor of insulin receptor catalytic activity, the growth factor receptor binding protein 14 (Grb14) in liver. Indeed, Grb14 knockdown enhanced hepatic insulin signaling but also dramatically inhibited de novo fatty acid synthesis. In the liver of obese and insulin-resistant mice, downregulation of Grb14 markedly decreased blood glucose and improved liver steatosis. Mechanistic analyses showed that upon Grb14 knockdown, the release of p62/sqstm1, a partner of Grb14, activated the transcription factor nuclear factor erythroid-2-related factor 2 (Nrf2), which in turn repressed the lipogenic nuclear liver X receptor (LXR). Our study reveals that Grb14 acts as a new signaling node that regulates lipogenesis and modulates insulin sensitivity in the liver by acting at a crossroad between the insulin receptor and the p62-Nrf2-LXR signaling pathways.
authors.affiliation: INSERM, U1016, Institut Cochin, Paris, France CNRS, UMR8104, Paris, France Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Popineau
authors.affiliation: INSERM, U1016, Institut Cochin, Paris, France CNRS, UMR8104, Paris, France Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Lucille
authors.initials: L
authors.lastname: Morzyglod
authors.affiliation: INSERM, U1016, Institut Cochin, Paris, France CNRS, UMR8104, Paris, France Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Nadège
authors.initials: N
authors.lastname: Carré
authors.affiliation: INSERM, U1016, Institut Cochin, Paris, France CNRS, UMR8104, Paris, France Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Michèle
authors.initials: M
authors.lastname: Caüzac
authors.affiliation: INSERM, U1016, Institut Cochin, Paris, France CNRS, UMR8104, Paris, France Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Bossard
authors.affiliation: INSERM, U1016, Institut Cochin, Paris, France CNRS, UMR8104, Paris, France Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Carina
authors.initials: C
authors.lastname: Prip-Buus
authors.affiliation: INSERM, U1016, Institut Cochin, Paris, France CNRS, UMR8104, Paris, France Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Lenoir
authors.affiliation: INSERM, U1016, Institut Cochin, Paris, France CNRS, UMR8104, Paris, France Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Ragazzon
authors.affiliation: INSERM, U1016, Institut Cochin, Paris, France CNRS, UMR8104, Paris, France Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Fauveau
authors.affiliation: INSERM U1043, Toulouse, France CNRS, unité 5282, Toulouse, France IRSD, INSERM, INRA, ENVT, UPS, Toulouse, France.
authors.forename: Lorenne
authors.initials: L
authors.lastname: Robert
authors.affiliation: INSERM, U1016, Institut Cochin, Paris, France CNRS, UMR8104, Paris, France Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Guilmeau
authors.affiliation: INSERM, U1016, Institut Cochin, Paris, France CNRS, UMR8104, Paris, France Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Postic
authors.affiliation: Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Komatsu
authors.affiliation: INSERM U1043, Toulouse, France CNRS, unité 5282, Toulouse, France IRSD, INSERM, INRA, ENVT, UPS, Toulouse, France.
authors.forename: François
authors.initials: F
authors.lastname: Canonne-Hergaux
authors.affiliation: Institut National de la Recherche Agronomique, ToxAlim Unité Mixte de Recherche 1331, Toulouse, France Université de Toulouse, INP, UPS, ToxAlim, Toulouse, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Guillou
authors.affiliation: INSERM, U1016, Institut Cochin, Paris, France CNRS, UMR8104, Paris, France Université Paris Descartes, Sorbonne Paris Cité, Paris, France anne-francoise.burnol@inserm.fr.
authors.forename: Anne-Françoise
authors.initials: AF
authors.lastname: Burnol
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D007333:Insulin Resistance; D050155:Lipogenesis; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D000071518:Liver X Receptors / Q000378:metabolism; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019941:Cyclin-Dependent Kinase Inhibitor p16; C490977:Grb14 protein, mouse; D000071518:Liver X Receptors; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D011506:Proteins; D011972:Receptor, Insulin