Research

Our research centers on the mechanisms whereby hydrophobic lipid molecules regulate nutrient metabolism and energy homeostasis. We seek to identify new molecular targets that could be leveraged in the management of obesity and its common metabolic complications, including metabolic dysfunction-associated steatotic liver disease and type 2 diabetes. 

Our interests include the role of lipid-sensing steroidogenic acute regulatory transfer related (START) domain proteins in lipid and glucose metabolism. START domains bind hydrophobic ligands, including phospholipids, cholesterol and fatty acids. Our laboratory has described novel roles for lipid-binding START domain proteins in metabolic control within the liver, as well as in whole body energy homeostasis. 

Phosphatidylcholine transfer protein/StarD2 and Thioesterase superfamily member 2

We have demonstrated that the START domain protein StarD2, also known as phosphatidylcholine transfer protein (PC-TP) plays a critical role in governing hepatic insulin sensitivity. Mice lacking PC-TP 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. Importantly, we have shown the fatty acyl-CoA thioesterase superfamily member 2 (Them2; synonym acyl-CoA thioesterase 13, Acot13) is an interacting partner of PC-TP and is activated upon binding PC-TP. We have further demonstrated that Them2 in turn plays a key role in regulating hepatic lipid and glucose metabolism, as well as energy homeostasis. 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. Our research suggests that PC-TP functions as a sensor of membrane phosphatidylcholine composition, which in turn regulates lipid and glucose metabolism. 

StarD14/Thioesterase superfamily member 1

In separate studies, we have demonstrated that StarD14 (synonyms Them1 and Acot11), a long-chain Acot that also comprises a C-terminal START domain, is highly enriched in brown adipose tissue and plays a major role in regulating energy homeostasis. Mice lacking Them1 are highly resistant to diet-induced obesity, diabetes and inflammation. We have developed evidence that Them1 functions as a fatty acid sensor that controls energy expenditure in brown adipose tissue by limiting access of free fatty acids to mitochondria and by reducing thermogenic gene expression. To conserved energy, we have shown that Them1 suppresses thermogenesis by forming a biomolecular condensate at the interface between lipid droplets and mitochondria within brown adipocytes. By contrast, during periods of increased demand for thermogenesis (e.g. cold exposure), Them1 is relocated to the nucleus where it controls the expression of genes that resupply energy substrates.  We have recently developed small molecule inhibitors of Them1 that show promise for the treatment of obesity-associated disorders by increased energy expenditure in thermogenic tissues.

StarD15/Acyl-CoA thioesterase 12

We have also undertaken studies of StarD15 (synonym Acot12), a short-chain Acot that principally hydrolyzes acetyl-CoA to acetate plus CoA.  Acot12 is enriched liver and small intestine.  The lipid ligand of its C-terminal START domain has not been identified.  However, we have demonstrated key roles for Acot12 in hepatic tryglericide metabolism, especially during fasting, and in the maintenance of intestinal barrier function and lipid absorption.