Fructose consumption has sharply risen and studies have shown that fructose can cause a variety of adverse effects, such as inducing insulin resistance, weight gain, and leptin resistance in animals and humans. In particular, fructose has been shown to increase hepatic fat synthesis and decrease hepatic fat oxidation, suggesting that fructose contributes to the pathogenesis of nonalcoholic fatty liver disease. We have identified that the rapid metabolism of fructose by ketohexokinase-C (KHKC) may be the key mechanism driving the adverse effects of fructose. Thus, we hypothesize that inhibition of KHKC provides a novel mechanism as a target for the development of a therapeutic agent to ameliorate fructose-induced fatty liver. [We propose to utilize two botanicals, Cinnamomum cassia (cinnamon) and Camillia sinensis var. assamica (Ceylon tea), which have been identified to have in vitro inhibitory effects on KHKC.] The objectives of the project are to determine the effectiveness of inhibiting KHKC by phytochemicals of cinnamon and tea on ameliorating (1) fructose-induced ATP depletion, (2) fructose-induced increase in hepatic fat synthesis and decrease in hepatic fat oxidation, and (3) the development of fructose-induced fatty liver. The findings from these studies will advance our understanding by validating KHKC as an important target for the development of therapies to prevent and treat fructose-induced fatty liver. During the proposed 5-year award period, the applicant will develop new skills and will increase her knowledge in the field of drug discovery and development, in particular working with botanicals as a therapeutic source. The award will provide the applicant the necessary training to become an independent scientist through both didactic programs and lectures and by facilitating interactions with researchers in different departments and institutions. The applicant has established an advisory committee that will provide her with excellent mentorship. As her primary mentor, Dr. Richard Johnson is one of the leading researchers in fructose- and uric acid-induced pathways in endothelial dysfunction, metabolic syndrome, kidney disease, and fatty liver disease. As Head of the Division of Renal Diseases and Hypertension at the University of Colorado Anschutz Medical Campus, Dr. Johnson will provide the applicant access to the necessary facilities and equipment to successfully complete her proposed studies. In addition, Dr. Michael Wempe, Associate Research Professor in the Department of Pharmaceutical Sciences and Director of the Medicinal Chemistry Core Facility, has extensive experience in medicinal chemistry. As her co-mentor, Dr. Wempe will supervise the applicant's training in drug discovery and development. In addition, Dr. Tiffany Weir, an Assistant Professor in the Department of Food Science and Human Nutrition at Colorado State University, will also be Dr. Le's co-mentor. She has extensive background in isolating and identifying plant-based compounds using both traditional bio-activity guided fractionation as well as metabolomics approaches, and thus, will train Dr. Le in the isolation and characterization of natural products. The applicant will also rely on the expertise of Dr. Hugo Rosen, Professor of Medicine and Immunology and Division Head of Gastro & Hepatology, and Dr. Miguel Lanaspa-Garcia, Assistant Research Professor in the Department of Renal Medicine. Dr. Rosen will consult on the histological analysis of fatty liver and Dr. Lanaspa-Garcia will consult on the design of in vitro and in vivo studies.
Fructose has been shown to induce a variety of adverse effects and has been suggested to contribute to the pathogenesis of nonalcoholic fatty liver disease. Ketohexokinase-C (KHKC) is the enzyme responsible for the rapid metabolism of fructose, which is potentially the key mechanism in stimulating fructose's adverse effects. The proposed project will evaluate the innovative therapeutic approach of utilizing botanicals to develop specific inhibitors of KHKC for the prevention and treatment of nonalcoholic fatty liver disease.