Numerous disease states are associated with having a fatty liver. These include obesity, atherosclerosis and insulin resistance. Because the liver can make its own fat, dietary restriction does not treat fatty liver diseases. The liver makes fatty acids from simple precursors, such as lactic acid. lactate enter the liver from the bloodstream, through the action of ATP-independent transport (“pump”) proteins..The driving force for the lactate pump is the release of protons. The lactate pump is a member of the monocarboxylate transporter family. Proteins in this family transport a range of monocarboxylic acids across cell membranes.
Developing small-molecule inhibitors of lactate pumps could lead to drugs for treating fatty liver diseases. There are no known inhibitors of the pump. This is because there are no know assays for pump protein activity. There are crystal structures of prokaryotic lactate pump proteins. Through a collaborator, we have access to unique, stable human liver cell lines with overexpressed lactate pumps. Structural data are not available. This makes reliable structure-based drug design impossible.
Phosphine-derived fluorescent probes will be used to develop appropriate fluorescence-based assays. When attached to a fluorophore, phosphines quench fluorescence by photoinduced electron transfer (PET) from the phosphorus lone pair. When the phosphine is oxidized to the phosphine oxide, the probes become fluorescent again. |