Salih Wakil Lab

Dr. Wakil's early studies of the mechanisms of fatty acid synthesis established the basis for the current understanding of this vital process in biological systems. Dr. Wakil demonstrated the requirement of ATP and stimulatory effect of carbon dioxide on fatty acid synthesis from acetyl-CoA, and showed that long-chain fatty acids are synthesized by a system independent of beta-oxidation. His contributions in this area also include the discovery of the function of biotin (vitamin H) as the prosthetic group of one of the active enzymes, and the identification of malonyl-CoA as the source of the C2 units in the de novo synthesis of long-chain fatty acids, and their elongation, in animal tissues. These observations led to the discovery of acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), the two key enzymes of fatty acid synthesis. His laboratory was the first to identify these multifunctional enzymes and to delineate the structure and mechanisms of their actions. He also has made contributions with respect to their genetic regulation.

Dr. Wakil's group also found that the animal ACC enzyme, including that of the human, is present in two isoforms, ACC1 and ACC2. The cDNAs of both isoforms have been cloned and sequenced, and have been expressed in appropriate expression systems in order to study the structure-function relationships of the isoforms. The ACCs are highly regulated by both allosteric and covalent modifications, many of which are controlled by hormones such as insulin, glucagon, epinephrine, and growth hormones. The amino acid terminal sequences of the two ACC isoforms were identified and shown to be essential for the cellular location. The ACC1 isomer is located in the cytoplasm of the cell, and its malonyl product is utilized in fatty acid synthesis by FAS. ACC2, on the other hand, with its hydrophobic N-terminus, is associated with the mitochondrial outer membrane, and its malonyl CoA product regulates fatty acid entry into the mitochondria for their beta-oxidation and energy production. ACC1 knockout mice led to embryonic fatality, whereas ACC2 -/- mutant mice have a normal life span and a higher fatty acid oxidation rate, and accumulate 50 percent less fat in their adipose tissue than wild-type mice.

The animal FAS is another remarkable multifunctional enzyme; it contains seven catalytic activities plus a site for the acyl-carrier protein, where the acyl group is chain-elongated and reduced. The partial activities of these enzymes were studied in both pro- and eucaryote organisms. The human FAS cDNA has been studied and expressed; sufficient quantities of the active enzyme have been obtained for study, and its structure and function have been investigated.

Dr. Wakil has made landmark contributions that have illuminated the understanding of fatty acid metabolism and the metabolic syndrome. His experimental insights into the mechanisms and physiology of fat metabolism have shed new light on the process of normal metabolism, and provided potential new targets for therapeutic intervention against widely proliferating human disorders and diseases such as obesity, type 2 diabetes, heart disease, and various forms of cancer.

Continuing their research on the metabolic syndrome, Dr. Wakil and his collaborators currently are focusing on studies involving a prospective anti-obesity pharmaceutical intervention. Earlier, they discovered a small molecule, FGH1001 (called “fatostatin” in related publications), which 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. One of Dr. Wakil's departmental colleagues, Dr. Motonari Uesugi, now a professor at Kyoto University in Japan and an adjunct professor at Baylor, 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 laboratory recently identified an orally available analog, FGH0019, which showed greater potency, oral bioavailability and efficacy in ob/ob mice. Dr. Wakil, Dr. Uesugi, and longtime Baylor College of Medicine collaborator Dr. Lutfi Abu-Elheiga are focusing on this compound to further investigate its potential as an effective anti-obesity agent through feasibility studies in rats. They expect the investigation to move on to other animals and eventually, to humans.