Our long-term goal is to determine the molecular mechanisms that control metabolic homeostasis and there by identify therapies for metabolic diseases. While metabolic regulation is vital for an organism?s function and survival, metabolic dysregulation associated with insulin resistance gives rise to diabetes, non-alcoholic fatty liver disease, dyslipidemia, and cardiovascular disease. The goal of this project is to define the role of hepatic TAZ (transcriptional co-activator with PDZ binding motif) in the regulation of glucose and lipid metabolism in normal and insulin resistant states. Proteins that regulate cell growth overlap with those that control metabolic homeostasis. Therefore, we determined whether TAZ, which is known to control proliferation, regulates hepatic metabolism. Using molecular, biochemical, and genetic approaches, we obtained preliminary data which reveal that TAZ, independent of the Hippo pathway, is a unique regulator of energy homeostasis in the liver. Hepatic TAZ protein is dynamically altered by fasting and feeding, and TAZ regulates the differential expression of gluconeogenic and lipogenic genes in response to fasting and feeding. However, in insulin resistant states, the dysregulation of TAZ leads to perturbations of both glucose and lipid homeostasis. To build on this preliminary work, we propose a series of molecular and mouse studies to delineate the molecular mechanisms whereby hepatic TAZ regulates glucose and lipid metabolism in physiologic and pathologic insulin resistant states.
Our aims are listed below.
Specific Aim 1 is to define the role of hepatic TAZ in the regulation of gluconeogenic gene expression and glucose homeostasis.
Specific Aim 2 is to define the role of hepatic TAZ in the regulation of de novo lipogenic gene expression and triglyceride homeostasis. We expect that our studies will define a new role for TAZ in metabolic regulation and will identify molecular mechanisms whereby glucose and lipid homeostasis are physiologically regulated. We also expect that our studies will provide mechanistic insights into the pathogenesis of insulin resistance, and thereby enable the development of therapies for insulin resistance-associated metabolic diseases, including diabetes, hepatosteatosis, dyslipidemia, and cardiovascular disease.
We propose to define the role of hepatic TAZ in the regulation of glucose and lipid homeostasis in normal and insulin resistant states. Deciphering the molecular mechanisms controlling metabolic regulation is crucial for the understanding of normal physiology and for developing new therapies for metabolic disorders. Therefore, we expect that our studies will advance our understanding of normal physiology as well as the pathogenesis of insulin resistance-associated metabolic disorders, which may uncover new opportunities for therapeutic intervention.
