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David E. Cohen, MD
Physician, Brigham and Women's Hospital
Visiting Professor of Medicine, Harvard Medical School

Brigham and Women's Hospital
Department of Medicine
75 Francis Street
Boston, MA 02115

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Research Narrative:

For the past eighteen years, my research program has focused on understanding the molecular regulation of hepatic lipid and glucose metabolism.  When taken together with my medical training, my formal education in chemistry and physics during college, physiology and biophysics during graduate school and then biochemistry and molecular biology as a postdoctoral research fellow have been invaluable in bringing a broad range of approaches to liver-oriented research.  Among my contributions has been to describe novel roles for phosphatidylcholine transfer protein (PC-TP) in the control of hepatic lipid and glucose homeostasis.  Because it binds phosphatidylcholines with high specificity and catalyzes their transfer between membranes in vitro, I originally proposed that PC-TP might play a role in the hepatocellular trafficking of biliary phospholipids to the canalicular membrane for secretion into bile and to the sinusoidal plasma membrane for incorporation into high density lipoprotein (HDL) particles.  In the course of these studies, I was the first to clone PC-TP, to characterize the gene and its transcription, and to express recombinant protein that we used to elucidate membrane-binding domains.  My laboratory crystallized PC-TP in complex with phosphatidylcholine, leading to our report of the three dimensional structure.  Studies in cell culture systems and Pctp-/- mice revealed much broader functions than anticipated in regulating metabolism.  In collaborative studies, I utilized hyperinsulinemic euglycemic clamp studies to demonstrate that Pctp-/- mice are highly sensitized to insulin action and are protected against diet-induced diabetes due to suppression of hepatic glucose production.  I further showed that Pctp-/- mice exhibit increased adaptive thermogenesis due to increased sensitivity of brown adipocytes to stimulation by norepinephrine.  I have discovered small molecule inhibitors of PC-TP, which show promise for increasing insulin sensitivity in cells and in mice.  In separate studies, my laboratory demonstrated that PC-TP binds and activates thioesterase superfamily member (Them) 2, a newly described fatty acyl-CoA thioesterase.  We have also demonstrated key roles of both Them1 and Them2 in regulating hepatic lipid and glucose metabolism, as well as energy homeostasis.

Harvard Medical School, 1987, MD