BBS Faculty Member - David Cohen

David Cohen

Department of Medicine
Harvard-MIT Division of Health Sciences and Technology

Brigham and Women's Hospital
Harvard Institutes of Medicine, Room 941
77 Avenue Louis Pasteur
Boston, MA 02115
Tel: 617-525-5090
Fax: 617-525-5100
Email: dcohen@partners.org
Lab Members: 5 postdoctoral fellows, 1 instructor, 3 technicians
Visit my lab page here.



Our research interests include the role of steroidogenic acute regulatory transfer-related (START) domain proteins in lipid and glucose metabolism, as well as the impact of obesity on hepatic cholesterol metabolism. The laboratory has described novel roles for lipid-binding START domain proteins in the control of lipid and glucose homeostasis in the liver.

My group identified a role for a phosphatidylcholine transfer protein (PC-TP/StarD2) in directing the transport of cholesterol molecules from peripheral tissues to liver for secretion into bile. Milestones in this research have included cloning and characterization of the Pctp gene, expression of recombinant protein and detailed structure-function analyses, studies of cellar function, solving the crystal structure of PC-TP, identification of key PC-TP-interacting proteins and detailed phenotyping of Pctp-/- mice. These studies have also revealed a global regulatory role for PC-TP in lipid and glucose homeostasis. We have shown that Pctp-/- mice are sensitized to hepatic insulin action, are relatively resistant to the development of type 2 diabetes and atherosclerosis, and exhibit more efficient brown fat-mediated thermogenesis. We have gone on to identify small molecule inhibitors of PC-TP and to demonstrate their efficacy in a mouse model of type 2 diabetes.

Because PC-TP contains no other functional domain, we reasoned that interactions with a separate protein might be critical for its biological activity. This led to our identification and characterization of thioesterase superfamily member 2 (Them2), which is activated upon binding PC-TP, as well as to the observation that PC-TP binds tuberous sclerosis complex 2 (TSC2), which plays a key role in insulin signaling.

In separate studies, we have demonstrated that Them1 (synonym StarD14), which is highly enriched in brown adipose tissue, plays a major role in regulating energy homeostasis. Mice lacking Them1 are highly resistant to diet-induced obesity, diabetes and inflammation. Studies are underway to define the molecular mechanisms of this metabolic regulation.



Last Update: 6/19/2014



Publications

Shishova EY, Stoll JM, Ersoy BA, Shrestha S, Scapa EF, Li Y, Niepel MW, Su Y, Jelicks LA, Stahl GL, Glicksman M, Gutierrez-Juarez R, Cuny GD, Cohen DE. Genetic ablation or chemical inhibition of phosphatidylcholine transfer protein attenuates diet-induced hepatic glucose production. Hepatology 2011; 54:664-74. PMCID: PMC3144994

Kang HW, Niepel MW, Han S, Kawano Y,
Cohen DE. Thioesterase superfamily member 2/Acyl-CoA thioesterase 13 (Them2/Acot13) regulates hepatic lipid and glucose metabolism. FASEB J 2012; 26:2209-21. PMCID: PMC3336778

Han S,
Cohen DE. Functional characterization of thioesterase superfamily member 1/acyl-CoA thioesterase 11: Implications for metabolic regulation. J Lipid Res 2012;53: 2620-31. PMCID: PMC3494255

Zhang Y, Li Y, Niepel MW, Kawano Y, Han S, Liu S, Marsili A, Larsen PR, Lee CH,
Cohen DE. Targeted deletion of Thioesterase superfamily member 1 promotes energy expenditure and protects against obesity and insulin resistance. Proc Natl Acad Sci USA 2012; 109:5417-22. PMCID: PMC3325675

Ersoy BA, Tarun A, D’Aquino K, Hancer NJ, Ukomadu C, White MF, Michel T, Manning BD,
Cohen DE. Phosphatidylcholine transfer protein interacts with thioesterase superfamily member 2 to attenuate insulin signaling. Sci. Signal. 2013;30:6:ra64.

Kang HW, Ozdemir C, Kawano Y, Vernochet C, Kahn CR, Hagen SJ,
Cohen DE. Thioesterase superfamily member 2/Acyl-CoA thioesterase 13 (Them2/Acot13) regulates adaptive thermogenesis in mice. J Biol Chem 2013:288:33376-86. PMCID: PMC3829184

Kawano Y, Ersoy BA, Li Y, Nishiumi S, Yoshida M,
Cohen DE. Thioesterase Superfamily Member 2 (Them2) and Phosphatidylcholine Transfer Protein (PC-TP) Interact To Promote Fatty Acid Oxidation and Control Glucose Utilization. Mol Cell Biol 2014; 34:2396-408. PMCID: PMC4054321



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