Obesity and diabetes negatively impact the development of cardiovascular disease. Our laboratory studies two specific underlying factors playing roles in the pathophysiology of obesity and diabetes leading to cardiovascular disease, namely the regulation of fatty acid metabolism and high density lipoprotein (HDL) metabolism. Obesity and diabetes are in part characterized by metabolic perturbations in fatty acid metabolism in insulin sensitive tissues and HDL metabolism by the liver. However, there is little known regarding the mechanisms governing intracellular fatty acid transport leading to triglyceride synthesis or oxidation nor mechanisms governing hepatic HDL metabolism.

Plasma levels of HDL are inversely correlated with atherosclerosis, the primary cause of premature death in industrialized countries. Multiple mechanisms have been implicated in atheroprotection by HDL including cholesterol efflux from macophages, anti-inflammatory properties and regulation of endothelial function. Understanding the mechanisms that regulate HDL metabolism will provide opportunities for modulating plasma levels of HDL leading to beneficial atheroprotective effects.

As one of our interests, we are studying the molecular mechanisms controlling HDL metabolism by the liver, the principal site of HDL uptake and metabolism in the body. As part of this plan we are studying the role of a multi-PDZ domain containing protein, PDZK1 that we have shown interacts with the HDL receptor SR-BI and to be essential for SR-BI expression. SR-BI is a plasma membrane glycoprotein essential for hepatic HDL uptake. We are currently utilizing our PDZK1 knockout mice generated in our laboratory to determine its role in regulating SR-BI function in the liver. In addition, we are using biochemical and genetic approaches to identify other protein partners of PDZK1. Moreover, we are interested in identifying the underlying mechanisms causing low HDL, and increased atherosclerosis in obesity and type 2 diabetes.

Obesity and diabetes are in part characterized by metabolic perturbations in fatty acid metabolism in insulin sensitive tissues. However, there is little known regarding the mechanisms governing intracellular fatty acid transport leading to triglyceride synthesis or oxidation.

As a separate interest of our laboratory we are determining the molecular mechanisms that regulate the partitioning of fatty acids for either triglyceride synthesis and storage in intracellular lipid droplets, or beta-oxidation. In order to understand the regulation of these pathways in disease, we are examining these processes in mouse models of obesity and type 2 diabetes. We have currently identified novel genes that regulate fatty acid partitioning and are generating gene targeted, transgenic mice, and in vitro systems to determine their functions. Therefore, the identification and characterization of novel factors regulating fatty acid transport our goals are to uncover fundamental pathways and mechanisms regulating cellular metabolism of fatty acids and ultimately provide new targets for the pharmacological intervention in obesity, type II diabetes, and cardiovascular disease.