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.

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.00170-16.

ACKNOWLEDGMENTS

We thank Florent Dumont and Franck Letourneur from the Plateform Génomique (Institut Cochin, Inserm U1016, Paris, France) for microarray experiments and analysis, Maryline Favier and the HISTIM facility for histochemistry analysis, Isabelle Lagoutte and the staff of the Cochin's animal facility, the Plateforme Biochimie from the Institut Claude Bernard, Paris, France, for plasma analysis, the Laboratoire de Thérapie Génique (Inserm UMR1089, Nantes, France) for the production of the p62 adenovirus, Ken Itoh (Japan) for anti-Nrf2 antibodies, and Roland Wolf (University of Dundee, United Kingdom) for the 8x-ARE reporter plasmid. C. Perret, R. Dentin, A. Leturque, S. Vaulont, M. Moldes, S. Lotersztajn, B. Cariou, and A. Iroz are gratefully acknowledged for helpful discussions and critical reading of the manuscript. Mice used in this study were housed in an animal facility equipped with the help of the Région Ile de France.

The work performed within the Département Hospitalo-Universitaire (DHU) Autoimmune and Hormonal Diseases (AUTHORS) was supported by grants from the Agence Nationale de la Recherche (ANR-06-Grb14, ANR-10-Wnt-Metaboliv, and ANR-09-JCJC-0057) and by the Fondation pour la Recherche Médicale (Labélisation Equipe). L.P. and L.M. are supported by a Ph.D. grant from the French Ministry of Research, and L.P. has a fellowship from the Fondation pour la Recherche Médicale.

We declare that we have no conflict of interest.

Additional information

Funding

Renaud Dentin was the recipient of Agence Nationale de la Recherche (ANR) grant ANR-09-JCJC-0057.