Research Projects

Systemic metabolism in higher organisms involves a complex network of pathways that regulate energy homeostasis through nutrient intake and disposition. Overwhelmed storage capacity leads to metabolic stress, promoting low-grade inflammation and metabolic dysfunction in organs like the liver, adipose, and skeletal muscle. This decline in metabolic health is one of the first indications of metabolic disease, resulting from an imbalance between energy intake and expenditure. Nutrient/diet dependent mechanisms impacting hepatic physiology are crucial. One such mechanism is O-GlcNAcylation, a dynamic and reversible post-translational modification (PTM) of ser/threo residues that regulates various cellular pathways. Disruption in protein glycosylation has been associated with various pathologies, including obesity, NAFLD, insulin resistance, diabetes, cardiovascular diseases, neurodegeneration, and cancer. Cell intrinsic metabolic sensors like SIRT6, a NAD+ dependent histone deacetylase, regulate various biological processes, including DNA repair, glucose and lipid metabolism, inflammation, oxidative stress, and lifespan through epigenetic and PTM regulation. SIRT6 influences hepatic health through mechanisms impacting the functioning of both hepatocytes and stellate cells. This project aims to delineate the role of nutrient dependent Glycosylation as a novel PTM for SIRT6 and its impact on hepatic physiology. Understanding these mechanisms will provide insights into how nutrition influences hepatic metabolic sensors and the origin of metabolic diseases, opening new avenues for targeted therapeutic interventions.