Team leader :
The research of our team of nutrients, metabolism and transcriptional response aims to understand how regulatory proteins, including transcription factors and transcriptional coregulators, act as sensors for molecules of nutritional, metabolic or pharmacological origin, and translate them into altered gene expression and protein patterns affecting metabolic function during metabolic diseases and cancer.
Over the last century, changes in lifestyle have resulted in an increase in the prevalence of the physiopathology of obesity and type 2 diabetes worldwide. Among complications associated with these two pathologies, Nonalcoholic Fatty Liver Disease (NAFLD) is emerging as the most common chronic liver disease in the western countries and is gaining increasing recognition as a component of the metabolic syndrome. The spectrum of NAFLD ranges from simple hepatic steatosis, with benign prognosis, to more severe forms including nonalcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC). Despite the fact that inert lipids, such as TG, are not toxic, accumulation of other lipid species, including diacylglycerols (DAG), ceramides, and fatty acids (FA), interfere with hepatocytes function and with their ability to respond to insulin. Obesity is also associated with chronic low-grade systemic inflammation, which is believed to contribute to the progression of NAFLD. Kupffer cells, which are specialized tissue macrophages in the liver, are the primary source of pro-inflammatory cytokines, contributing to the development of liver insulin resistance. Overall, it seems that defining cell types and sub-cellular compartments in which changes in levels of specific FA species occur may identify new avenues for potential prevention or treatment of NAFLD.
In this line of evidence, our research group was amongst the pioneers to unravel the contribution of the glucose-regulated transcription factor ChREBP (Carbohydrate Responsive Element Binding Protein) in metabolic control. We particularly found that ChREBP activity was induced in response to the activation of glucose metabolism in hepatocyte, leading to its nuclear translocation. Furthermore, we established how this transcription factor governs hepatic glycolysis and de novo lipid synthesis by being recruited to the promoter of glycolytic (LPK) and lipogenic genes (ACC, FAS, SCD1…). Perhaps most striking in this context was our discovery of the contribution of enhanced ChREBP transcriptional activity in NAFLD development during the physiopathology of obesity and type 2 diabetes.
Our team also identify the serine/threonine kinase SIK2 (Salt Inducible Kinase 2) as an energy sensor and effector, that fine-tune hepatic glucose and lipid metabolism. Our work demonstrated that increasing SIK2 activity, by either inhibiting hepatic glucose production or lipid synthesis, through the direct inhibition of the transcriptional coactivator CRTC2 (CREB Regulated Transciptional Coactivator 2) and ChREBP, is a valid therapeutic approach to stimulate oxidative metabolism to protect liver from the adverse consequences of fatty acid storage during obesity and type 2 diabetes. At the molecular level, our study particularly highlights that SIK2 regulates ChREBP transcriptional activity by acetylation in a p300-dependent manner.
More recently, in a search for new ChREBP coregulator partners, we identify the histone demethylase Phf2 (Plant Homeodomain Finger 2) as a new modulator of ChREBP function within the liver. Overall, by specifically erasing H3K9me2 methyl‐marks on the promoter of ChREBP-regulated genes, Phf2 facilitates incorporation of metabolic precursors into insulin sensitizing mono‐unsaturated fatty acids (MUFA), leading to NAFLD development unexpectedly dissociated from inflammation and insulin resistance. The concomitant activation of the transcription factor NFE2‐related factor 2 (Nrf2) further reroutes glucose fluxes towards the pentose phosphate pathway and glutathione biosynthesis, protecting liver from oxidative stress and fibrogenesis. Overall, our findings establish in mice and human a downstream epigenetic checkpoint, whereby Phf2, through facilitating H3K9me2 demethylation, protects liver from the pathogenic accumulation of lipids during hepatosteatosis development.
Since many of these signaling and transcriptional events contribute to the pathogenesis of common metabolic disorders (e.g. obesity, type 2 diabetes), our research paved the way for novel preventive and therapeutic strategies for these diseases. Although the research of the members of our team involves the elucidation of fundamental biological mechanisms, we are always preoccupied with the clinical relevance of our work, setting an example for biomedical researchers. Therefore, our laboratory has a track record of successful collaborations with clinicians, facilitating the transfer of our ideas from bench to bedside.
Our group will continue with its approach to elucidate how specific transcription factor and their associated proteins control metabolic pathways and impact on energy homeostasis. As in the past, we will use an integrative system approach, in which genetic mouse model will occupy a pivotal role. The main axes of our research also remain unchanged. Below, we briefly discuss the new approaches/strategies that will be used to advance knowledge in these domains.
ChREBP and associated proteins that control energy homeostasis
We already analyzed genetically engineered mouse models that specifically overexpress ChREBP or Phf2 expression in the liver. To further identify novel metabolic roles of this transcription factor and coactivator, we have recently developed, though classical Cre-LoxP strategy, new mouse models that will specifically lack ChREBP or Phf2 expression in other tissues (e.g. macrophages, adipocytes, pancreas…).
We will be testing the hypothesis that ChREBP and Phf2 control metabolism in various tissues, through the analysis of mice in which the ChREBP and/or Phf2 genes are deleted in the germ line or in a spatially and temporally controlled manner. These models will undergo extensive metabolic phenotypic characterization that will be combined with in depth cellular and molecular profiling enabling us: 1) to reconstruct the networks governed by ChREBP and Phf2; 2) to validate modulation of ChREBP and Phf2 signaling as a strategy to prevent and combat metabolic disease.
ChREBP and carcinogenesis
Since ChREBP is an important regulator of energy metabolism, it may represent in malignant cells, a new provider of the substrates required for biomass generation, by redirecting a significant fraction of glucose carbon into de novo lipogenesis and nucleotide biosynthesis. However, to date, the direct implication of ChREBP in tumor initiation and progression is poorly defined. Overall, we will determine if an increase of ChREBP activity can initiate tumor development and whether it can participate to the cancer progression. We will further decipher the molecular mechanisms involved in ChREBP-mediated tumor initiation and/or progression and will finally establish whether ChREBP inhibition could represent a valuable potential therapeutic target to improve drug resistance during cancer treatment.
Generation of transgenic mouse models
In vivo imaging
Integrative physiology and metabolism
Transcription factors and coregulators biology
Cellular and molecular biology
In vivo injection of recombinant adenovirus and associated-adenovirus (AAV)
Energy metabolism, metabolic syndrome, obesity, type 2 diabetes, dyslipidemia, inflammation, insulin résistance, fibrosis, cancer, proliferation, metabolic reprogramming.
Dentin R, Tomas-Cobos L, Foufelle F, Leopold J, Girard J, Postic C, Ferré P. Glucose 6-phosphate, rather than xylulose 5-phosphate, is required for the activation of ChREBP in response to glucose in the liver. J Hepatol. 2012 Jan;56(1):199-209.
Bricambert J, Miranda J, Benhamed F, Girard J, Postic C, Dentin R. Salt-inducible kinase 2 links transcriptional coactivator p300 phosphorylation to the prevention of ChREBP-dependent hepatic steatosis in mice. J Clin Invest. 2010 Dec;120(12):4316-31.
Dentin R, Liu Y, Koo SH, Hedrick S, Vargas T, Heredia J, Yates J 3rd, Montminy M. Insulin modulates gluconeogenesis by inhibition of the coactivator TORC2. Nature. 2007 Sep 20;449(7160):366-9.
Dentin R, Hedrick S, Xie J, Yates J 3rd, Montminy M. Hepatic glucose sensing via the CREB coactivator CRTC2. Science. 2008 Mar 7;319(5868):1402-5.
Dentin R, Benhamed F, Hainault I, Fauveau V, Foufelle F, Dyck JR, Girard J, Postic C. Liver-specific inhibition of ChREBP improves hepatic steatosis and insulin resistance in ob/ob mice. Diabetes. 2006 Aug;55(8):2159-70.
Recipient of the ERC starting grant program 2013
Recipient of the “projet émergence(s)” award from the city of Paris 2011
Recipient of the Apollinaire Bouchardat award 2011
Recipient of the G.B. Morgagni award 2010
Recipient of the ANR Young Investigator program 2009
Recipient of the Bettencourt Schueller Foundation award 2006
Recipient of the French endocrinology society award 2005
Member of the DHU (Département Hospitalo-Universitaire) AUTHORS «Maladies hormonales et auto-immunes» created in 2013.
Member of the French Diabetes Society (SFD).