Biological and Biomedical Science
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David E. Cohen

Department of Medicine
Harvard-MIT Division of Health Sciences and Technology
Brigham and Women's Hospital
Harvard Medical School
Thorn Building, Room 1405
75 Francis Street
Boston, MA 02115
Tel: (617) 525-7847
Fax: (617) 264-6368
Email: dcohen@partners.org
6 postdoctoral fellows, 1 technician

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 for secretion into bile. Consistent with their central function in reverse cholesterol transport, high density lipoproteins (HDL) are the principal source of biliary cholesterol. Hepatocellular secretion of phosphatidylcholines into blood and bile is critical for assembly of nascent preß-HDL particles and for biliary lipid secretion, respectively. 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 preß-HDL. Using PC-TP-deficient and wild type mice, we have developed evidence that PC-TP regulates reverse cholesterol transport. Data from these studies have also suggested a more global regulatory role in hepatic lipid homeostasis. Therefore, recent experiments have also been aimed at exploring the control of hepatic triglyceride metabolism using genetically engineered mice.

Considering its central role in lipid metabolism, a major effort in the laboratory has been focused on elucidating structure-function relationships of PC-TP, which is highly specific for binding phosphatidylcholines. 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 central b-sheet and an amphipathic C-terminal a-helix. The positively charged choline headgroup of the lipid engages in cation-p interactions within a cage formed by the faces of three aromatic residues. In addition, the crystal structure of PC-TP in complex with phosphatidylcholine 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 fatty liver disease, atherosclerosis and cholesterol gallstones. 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. This occurs by leptin action within the central nervous system. To further explore mechanisms of control, 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.

 

References:

  • Roderick SL, Chan WW, Agate DS, Olsen LR, Vetting MW, Rajashankar KR, Cohen DE. Structure of human phosphatidylcholine transfer protein in complex with its ligand. Nature Struct Biol 2002;9:507-11.
  • Pan H-J, Agate DS, King BL, Wu MK, Roderick SL, Leiter EH, Cohen DE. A polymorphism in New Zealand inbred mouse strains that inactivates phosphatidylcholine transfer protein. FEBS Lett 2006;580:5953-5958.
  • Kanno K, Wu MK, Agate DS, Fanelli BJ, Wagle N, Scapa EF, Ukomadu C, Cohen DE. Interacting proteins dictate function of the minimal START domain phosphatidylcholine transfer protein/StarD2. J Biol Chem 2007;282:30728-30736.
  • Lee A-H, Scapa EF, Cohen DE, Glimcher LH. Regulation of hepatic lipogenesis by the transcription factor XBP1. Science. 2008;13320:1492-1496.
  • Scapa EF, Pocai A, Wu MK, Gutierrez-Juarez R, Glenz L, Kanno K, Li H, Biddinger S, Jelicks LA, Rossetti L, Cohen DE. Regulation of energy substrate utilization and hepatic insulin sensitivity by phosphatidylcholine transfer protein/StarD2. FASEB J 2008;22:2579-2590.