UMIL is a member of the League of European Research Universities (LERU) and offers highest quality research and education recognized at the national and international levels. The mission of DiSFeB is to promote training and to organize research activities aimed at studying biochemical mechanisms of disease and identifying novel molecular targets in the areas of diabetes, obesity, atherosclerosis and metabolic disorders, neuroscience, toxicology.
Partner 3 team leader:
Associate Professor Maurizio Crestani
Dipartimento di scienze farmacologiche e biomolecolari (DiSFeB)
Maurizio Crestani’s team has long-time experience in metabolic pathways relevant to atherosclerosis, obesity and diabetes with strong background in epigenetics and transcription regulation of metabolic pathways and energy metabolism by nuclear receptors, coregulators and chromatin modifiers. We recently showed that specific histone deacetylases (HDACs) are chief epigenetic regulators in diabetes/obesity. We aim to unveil signalling pathways associated to diabetes/obesity and to bridge new knowledge to clinical applications.
The team discovered alternative regulatory pathways of bile acid synthesis involving epigenetic modifications by HDACs. They demonstrated for the first time that bile acids regulate glucose metabolism by repressing the expression of the gluconeogenic enzyme PEPCK. They showed the role of a-helix 3 and 11 of PPAR ligand binding domain in recruiting coregulators and receptor activation. The team profiled fatty acids, phospholipids and steroids in tissues of diabetic models. They also demonstrated the role of class I HDACs in energy metabolism in vivo and that their inhibition leads to “browning” of white fat and improves the diabetic/obese phenotype of db/db mice. Dr. Crestani has been coordinator of European projects FP5-NORTh and FP6-SOUTH, participated in the Marie Curie training network ATHERODIS and coordinates national projects funded by the Italian Ministry of Research and University and by private foundations.
The team of Dr. Crestani will contribute to the phenotyping of iPSCs and iPSC-derived hepatocytes in WP2 and of mouse models in WP5 and WP8 (Task 8.3). The team will perform targeted lipidomic analyses of CNS areas, biological fluids and the liver and will define the epigenome landscape by assessing histone modifications in iPSC-derived hepatocytes and in mice with humanised liver. Association of RNA polymerase II, coregulators, HDACs and transcription factors to promoters will also be determined. These data will be overlaid to transcriptomics data (Task 8.2) to correlate epigenetic modifications to gene transcription.
1. Galmozzi A, et al. (2013) Inhibition of Class I Histone Deacetylases Unveils a Mitochondrial Signature and Enhances Oxidative Metabolism in Skeletal Muscle and Adipose Tissue. Diabetes Mar;62(3):732-42.
2. Cermenati G, et al. (2012) Diabetes induced myelin abnormalities are associated with an altered lipid pattern: protective effects of LXR activation. J. Lipid Res. 53, 300-310.
3. Porcelli L, et al. (2012) Synthesis, characterisation and biological evaluation of ureidofibrate-like derivatives endowed with peroxisome proliferator-activated receptor activity. J. Med. Chem. 55, 37-54.
4. Pochetti G, et al. (2010) Structural insight into peroxisome proliferator-activated receptor g binding of two ureidofibrate-like enantiomers by molecular dynamics, cofactor interaction analysis and site-directed mutagenesis. J. Med. Chem. 53, 4354–4366.
5. Mitro N, et al. (2007) Insights in the regulation of cholesterol 7a-hydroxylase gene reveal a target for modulating bile acid synthesis. Hepatology 46, 885-897.