Research in the Abu-Elheiga Lab is focused on the hormonal and dietary regulation of fatty acid metabolism in diseases and adverse health conditions, particularly the contemporary epidemic of obesity and related complications such as diabetes and cardiac malfunction.
Roles of Acetyl-CoA Carboxylases, ACC1 and ACC2
For some time, our work has focused on understanding the roles of acetyl-CoA carboxylases, ACC1 and ACC2, in the regulation of fatty acid synthesis and oxidation as related to energy homeostasis. Our transgenic mice studies of ACC1 and ACC2 revealed that Acc1 null mutation resulted in embryonic lethality at 6.5 days, whereas ACC2 null mutants were found to have a normal life span, a higher fatty acid oxidation rate, and less fat than normal wild-type mice, which produce the enzyme. When given unlimited access to food, the mutant mice ate 20-30% more than wild-type mice but weighed about 10 percent less, and accumulated far less fat in their adipose tissue (Abu-Elheiga et al., Science 2001).
A subsequent study showed that ACC2 mutant mice which were fed a high-fat, high-carbohydrate diet were resistant to obesity and diabetes, in contrast to wild-type mice controls on the same diet which became type-2 diabetic, with hyperglycemic and hyperinsulinemic status. The mutant mice weighed less than their cohorts and had significantly higher fatty acid oxidation rates (Abu-Elheiga et al, PNAS 2003.) , We have conducted further studies in ACC2 knockout mice which have provided additionally revealing data with respect to the liver and heart.
Prospective Anti-Obesity Pharmaceutical Intervention Studies
Recently, collaborators and our lab members have been focusing on studies involving a prospective anti-obesity pharmaceutical intervention. We discovered that a small synthetic molecule, which we named FGH1001 (called "fatostatin" in related publications), inhibits the activation of sterol regulatory element-binding proteins (SREBPs) -1 and -2, transcription factors that function as master regulators of fat and lipid synthesis.
A former member of our department, Dr. Motonari Uesugi, who is now a professor at Kyoto University in Japan and an adjunct professor at Baylor College of Medicine, discovered the compound by screening a library of an estimated 10,000 compounds. FGH1001 blocked increases in body weight, blood glucose and hepatic fat accumulation in obese ob/ob mice fed a high-fat, high-carbohydrate diet, even under uncontrolled food intake. In working to optimize this compound for potential use as a therapeutic anti-obesity intervention in human beings, Dr. Uesugi’s lab recently identified an orally available analog, FGH0019, which showed greater potency, oral bioavailability and efficacy in ob/ob mice. Dr. Uesugi, Biochemistry Department chair emeritus and professor Salih Wakil and our lab plan to further investigate the potential of this compound as an effective anti-obesity agent through feasibility studies in rats. We expect the investigation to move on to other animals and eventually to humans.