Our research is focused on the molecular and cellular mechanisms by which the liver clears cholesterol from the blood and processes it for elimination from the body. Our group has identified a role for a specific lipid binding protein, phosphatidylcholine transfer protein (PC-TP; StarD2), in directing the movement of cholesterol within liver cells. We are also interested in the impact of obesity on hepatic cholesterol metabolism.
PC-TP is a member of the START domain superfamily of functionally diverse hydrophobic ligand binding proteins and is highly expressed in liver. Earlier studies from our laboratory tested the hypothesis that PC-TP plays a key role in reverse cholesterol transport, the metabolic pathway for movement of insoluble cholesterol molecules from peripheral tissues to liver. Consistent with their central function in reverse cholesterol transport, high density lipoproteins (HDL) are the principal source of cholesterol that is eliminated by the liver. Hepatocellular secretion of phosphatidylcholines is critical for assembly of nascent preß-HDL particles. Our studies in transfected cell lines, as well as mouse peritoneal macrophages have shown that PC-TP promotes apolipoprotein A-I-mediated cellular efflux of phospholipid and cholesterol as HDL. Using PC-TP-deficient and wild type mice, we have developed evidence that PC-TP regulates reverse cholesterol transport. These studies have also suggested a more global regulatory role in hepatic lipid homeostasis. Experiments are underway to explore the control of hepatic triglyceride metabolism.
Considering its central role in lipid metabolism, a major effort in the laboratory has been focused on elucidating structure-function relationships of PC-TP. We have determined the crystal structure of human PC-TP in complex with phosphatidylcholine. This revealed that a single well-ordered phosphatidylcholine molecule occupies a tunnel formed primarily by a centralb-sheet and an amphipathic C-terminal a-helix. This crystal structure demonstrates that a major conformational change is required for lipid binding. The structural basis for this conformational change will be elucidated by solving the crystal structure of apoPC-TP (i.e. PC-TP in the absence of phosphatidylcholine).
Together with diabetes, altered cholesterol homeostasis is frequently associated with obesity and contributes to increased risks for atherosclerosis and fatty liver disease. Elevated plasma leptin concentrations in obese humans suggest resistance to this hormone’s biological activities. We have shown an important function of leptin is the regulation of hepatic cholesterol metabolism. We are utilizing selected rodent models to identify specific molecular pathways by which leptin promotes cholesterol elimination from the body. The results should provide new insights into the pathophysiology of common obesity-related diseases.
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