Regulation of liver insulin sensitivity and energy homeostasis by the

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Proposition de sujet de thèse à l’appui d’une demande de contrat doctoral 2016-2017
Renseignements relatifs à l’Unité de Recherche :
Label et intitulé : Institut Cochin, Inserm U1016-CNRS UMR 8104-Université Paris Descartes
Nom et prénom du Directeur : Pierre-Olivier Couraud
Téléphone : 01 40 51 64 57
Télécopie : 01 40 51 64 73
courriel : [email protected]
Renseignements relatifs à l’Equipe :
Nom de l’Equipe d’Accueil : Signalisation de l’insuline et du glucose, glucotoxicité
Nom et prénom du responsable : Catherine Postic
Qualité du responsable : DR CNRS
Téléphone :
01 53 73 27 07
Télécopie : 04 44 41 24 21
courriel : [email protected]
Renseignements relatifs au sujet de thèse :
Nom et prénom du Directeur de thèse (HDR) : Anne-Françoise Burnol
Qualité : DR CNRS
Téléphone :
01 53 73 27 09
Télécopie : 01 44 41 24 21
courriel : [email protected]
Titre du sujet proposé :
(en français) : Régulation de la sensibilité à l’insuline et de l’homéostasie énergétique hépatiques par la
protéine adaptatrice p62/sqstm1
(en anglais) : Regulation of liver insulin sensitivity and energy homeostasis by the molecular adapter
p62/sqstm1
Département (cocher le département correspondant au sujet de thèse qui n’est pas obligatoirement le
vôtre) :
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Biologie Cellulaire et moléculaire, Physiologie et Physiopathologie
Immunologie
Développement Génétique Neurobiologie et Vieillissement
Infectiologie, Microbiologie
Summary (5 lignes maximum) : The molecular adapter p62 is involved in various processes crucial for
metabolic and structural cellular homeostasis, such as inflammation, autophagy or oxidative stress. The
aim of this project is to elucidate its role in the control of liver energy metabolism and insulin sensitivity
and its contribution to the agravation of begnin steatosis towards steatohepatitis in the NAFLD (nonalcoholic fatty liver disease) syndrome.
Proposition de sujet de thèse à l’appui d’une demande de contrat doctoral 2015-2016
(l'ensemble de cette fiche ne doit pas dépasser 1 page)
Nom, prénom du directeur de l'unité de recherche : Pierre-Olivier Couraud
Numéro de l'unité de recherche (et établissement de rattachement) : Institut Cochin InsermU1016
Nom, prénom du responsable de l'équipe d'accueil (EAD) : Catherine Postic
Nom, prénom du directeur de thèse : Anne-Françoise Burnol
Titre du sujet de thèse proposé : Regulation of liver insulin sensitivity and energy homeostasis by the molecular
adapter p62/sqstm1
Citer 5 mots clés : lipid metabolism; glucose production; oxidative stress; NAFLD; insulin
Candidat pressenti :
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OUI
NON
Contenu scientifique du programme de la thèse (en anglais)
Non alcoholic fatty liver disease (NAFLD) is an evolutive syndrome affecting nearly one third of the population and
80% of obese people in western countries. Simple steatosis is begnin, but in the presence of inflammation or
oxidative stress it can evolve towards more severe forms such as nonalcoholic steatohepatitis (NASH). The scafold
protein p62/sqstm1 is implicated in cellular homeostasis through the regulation of multiple pathways. p62 is
involved in the inflammatory response through stimulation of the NFB pathway and in the activation of the Nrf2
anti-oxidant response. p62 is also a substrate and a receptor of autophagy. Chronic deregulation of p62 expression
is associated with hepatotoxicity and tumorigenesis, but the physiological role of liver p62 still remains obscur.
Recent studies, including ours, suggest that p62 is implicated in the regulation of liver metabolic homeostasis. This
function involves complex relationships with the mTORC1 complex, a crucial nutrient sensor controlling energy
homeostasis acting also as a potent inhibitor of autophagy. We recently demonstrated that an acute increase in
p62 availability represses liver de novo lipogenesis by activating Nrf2. Furthermore, as shown in mouse models of
obesity, an appropriate autophagy flux is required for liver metabolic homeostasis, and alteration of this pathway is
directly involved in the development of insulin resistance.
The objective of this project is to elucidate the physiological role of p62 in the control of liver insulin sensitivity and
energy homeostasis and to address its contribution in the development of insulin resistance and hepatic steatosis.
We developped recombinant viruses (adeno or AAV) to knock-down p62 (p62-shRNA) or to overexpress either fulllength p62 (p62) or a shorter isoform potentially altered for Nrf2 activation (p62), specifically in mouse liver or
primary cultured mouse hepatocytes. In parallel we are also generating a genetic mouse model with an hepatospecific inducible deletion of p62. Mice will be studied using dynamic metabolic tests and their liver will be analyzed
(metabolic gene expression by qRT-PCR and Western blot ; lipid content ; transcriptomics ; proteomics). p62
phosphorylation state, which is determinant for its activities, will be more particularly investigated. We also will
determine whether silencing liver p62 in mouse models of obesity allows to reverse insulin resistance and
metabolic alterations. A collaboration set up with Pr. Pattou’s laboratory will help correlating p62 expression and
phosphorylation with steatosis and insulin sensitivity in liver biopsies from the human ABOS cohort.
Unraveling the role of p62 in the regulation of liver energy homeostasis and insulin sensitivity will help establishing
whether it can be considered as a new therapeutic target in the treatment of NAFLD, from the early development of
hepatic steatosis to the more severe forms of NASH.
Indiquez les cinq meilleures publications récentes de l’équipe:
Popineau L, Morzyglod L, Carré N, Caüzac M, Bossard P, Prip-Buus C, Lenoir V, Ragazzon B, Fauveau V, Robert L, Guilmeau
S, Postic C, Komatsu M, Canonne-Hergaux F, Guillou H, Burnol AF. A novel Grb14-mediated cross-talk between insulin and
p62/Nrf2 pathways regulates liver lipogenesis and selective insulin resistance. Mol. Cell. Biol. In revision.
Perdereau D, Cailliau K, Browaeys-Poly E, Lescuyer A, Carré N, Benhamed F, Goenaga D, Burnol AF. 2015. Insulin-induced
cell division is controlled by the adaptor Grb14 in a Chfr-dependent manner. Cell Signal. 27: 798-806.
Nevazanyy Y, Montagnac G, Russell RC, Morzyglod L, Burnol AF, Guan KL, Pende M, Panazyuk G. 2015. Class III PI3K
regulates organismal glucose homeostasis by providing negative feedback on hepatic insulin signalling. Nat Commun
6:8283.
Marmier S, Dentin R, Daujat-Chavanieu M, Guillou H, Bertrand-Michel J, Gerbal-Chaloin S, Girard J, Lotersztajn S, Postic C.
2015. Novel role for carbohydrate responsive element binding protein in the control of ethanol metabolism and susceptibility
to binge drinking. Hepatology 62:1086-1100.
Benhamed F, Denechaud P-D, Lemoine M, Robichon C, Moldes M, Bertrand-Michel J, Ratziu V, Serfaty L, Housset C, Capeau
J, Girard J, Guillou H, Postic C. 2012. The lipogenic transcription factor ChREBP dissociates hepatic steatosis from insulin
resistance in mice and humans. J. Clin. Invest. 122 : 2176-2194.