Hepatic Dach1 regulates lipid metabolism

Individuals with type 2 diabetes have a 2–4-fold increase in their lifetime risk of cardiovascular diseases, arising from lipid abnormalities. The PI has identified a pathway activated by calcium/calmodulin-dependent protein kinase II (CaMKII) that inhibits insulin signaling. She went on to characterize the corepressor Dachshund homolog 1 (Dach1) as a key effector of the calmodulin-kinase pathway in liver. Hepatic Dach1 levels increase in obese mice and humans, and Dach1 inhibition protects against hyperinsulinemia and hyperglycemia. In addition, hepatocyte-specific Dach1 deletion leads to a decrease of plasma cholesterol levels. In this PF grant, the PI is investigating whether Dach1-mediated co-repression links insulin resistance with abnormal lipid and cholesterol metabolism.