Final Report Summary - LIPIDOLIV (Role of the transcription factor ChREBP and its associated proteins in the development and progression of NAFLD.)
The research of our team aimed to better understand how regulatory proteins, including specific transcription factors and transcriptional coregulators, act as sensors for molecules of nutritional, metabolic or pharmacological origin, and then translate them into altered patterns of gene expression affecting metabolic function during metabolic diseases and cancer. We specifically aimed to determine how nutrients, such as glucose, trough the regulation of the transcription factor ChREBP (Carbohydrate Responsive Element Binding Protein) favor the development and progression of Non Alcoholic Fatty Liver Disease (NAFLD), which usually refers to the build-up of neutral lipids within the hepatocytes and which is emerging as the most common chronic liver disease in western countries. The spectrum of NAFLD indeed ranges from simple hepatic steatosis with benign prognosis, to more severe forms including nonalcoholic steatohepatitis (NASH), cirrhosis and liver cancer named hepatocellular carcinoma (HCC). In particular, since the transcription factor ChREBP has been identified by our team as the major mediator of glucose action on glycolysis, nucleotide and de novo fatty acid synthesis, it may represent in malignant cells, a new provider of the substrates required for biomass generation during cell proliferation and cancer development.
Overall, using metabolic tracing studies, we found that ChREBP activation reroutes glucose fluxes into the pentose phosphate and lipogenic pathways to enhance nucleotide and de novo fatty acid synthesis, which both constitute building blocks used during cell proliferation. Furthermore, ChREBP also reroutes glutamine (non-essential amino acid) fluxes through de novo pyrimide biosynthesis to support cell proliferation. Overall, increased activation of ChREBP transcriptional activity favors NAFLD development and tumor initiation and growth by rewiring glucose and glutamine metabolism into specific anabolic pathways to sustain high cancer cell’s proliferation rate. Supporting these observations, ChREBP expression was upregulated during hepatocellular carcinoma development and signed specifically tumors with poor prognosis in human. Altogether, these results provided a new mechanism of how glucose and glutamine metabolism, through the regulation of ChREBP activity, contributed to tumorigenicity during HCC initiation and growth. This discovery light the way to the identification of potential new therapeutics for HCC treatment in the future. In this line of evidence, we have identified through the course of the ERC project the first pharmacological ChREBP inhibitors. These specific inhibitors have been shown to inhibit cell proliferation and HCC tumor development in different HCC mouse models.
In conclusion, our research program provides a better understanding of the role of the transcription factor ChREBP in the development and progression of NAFLD to NASH and HCC. It specifically deciphers the function of ChREBP in hepatocytes and provides important information on the molecular events leading to the development of HCC. Since many of these signaling and transcriptional events under the control of ChREBP also 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.
Overall, using metabolic tracing studies, we found that ChREBP activation reroutes glucose fluxes into the pentose phosphate and lipogenic pathways to enhance nucleotide and de novo fatty acid synthesis, which both constitute building blocks used during cell proliferation. Furthermore, ChREBP also reroutes glutamine (non-essential amino acid) fluxes through de novo pyrimide biosynthesis to support cell proliferation. Overall, increased activation of ChREBP transcriptional activity favors NAFLD development and tumor initiation and growth by rewiring glucose and glutamine metabolism into specific anabolic pathways to sustain high cancer cell’s proliferation rate. Supporting these observations, ChREBP expression was upregulated during hepatocellular carcinoma development and signed specifically tumors with poor prognosis in human. Altogether, these results provided a new mechanism of how glucose and glutamine metabolism, through the regulation of ChREBP activity, contributed to tumorigenicity during HCC initiation and growth. This discovery light the way to the identification of potential new therapeutics for HCC treatment in the future. In this line of evidence, we have identified through the course of the ERC project the first pharmacological ChREBP inhibitors. These specific inhibitors have been shown to inhibit cell proliferation and HCC tumor development in different HCC mouse models.
In conclusion, our research program provides a better understanding of the role of the transcription factor ChREBP in the development and progression of NAFLD to NASH and HCC. It specifically deciphers the function of ChREBP in hepatocytes and provides important information on the molecular events leading to the development of HCC. Since many of these signaling and transcriptional events under the control of ChREBP also 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.