David E. Cohen, M.D., Ph.D.

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.

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.

Scapa EF, Pocai A, Wu MK, Gutierrez-Juarez R, Glenz L, Kanno K, Li H, Biddinger S, Jelicks L, Rossetti L, Cohen DE. Regulation of energy substrate utilization and hepatic insulin sensitivity by phosphatidylcholine transfer protein/StarD2. FASEB J 2008;22:2579-2590.

Wagle N, Xian J, Shishova EY, Wei J, Glicksman MA, Cuny GD, Stein RL, Cohen DE. Small molecule inhibitors of phosphatidylcholine transfer protein/StarD2 identified by high throughput screening. Anal Biochem 2008;383:85-92.

Kang H, Ribich S, Kim BW, Hagen SJ, Bianco AC, Cohen DE. Mice lacking phosphatidylcholine transfer protein/StarD2 exhibit increased adaptive thermogenesis and enlarged mitochondria in brown adipose tissue. J Lipid Res 2009;50:2212-2221.

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.