The mitochondrial pyruvate dehydrogenase complex (PDC) is the gate-keeping enzyme that controls glucose oxidation through the Krebs cycle. PDC is negatively regulated by pyruvate dehydrogenase kinase isoforms 1-4 (PDKs 1-4). In patients with type 1 and type 2 diabetes (T1D and T2D), PDK 4 is up-regulated resulting in the inhibition of glucose oxidation. Similar to PDC, the mitochondrial branched-chain ?-ketoacid dehydrogenase complex (BCKDC) is the rate-limiting step that sets pace for the oxidative degradation of branched-chain amino acids (BCAA) also via the Krebs cycle. Similar to PDC, BCKDC is negatively regulated by the intrinsic BCKDC kinase (BDK). In patients with obesity and T2D, hepatic BDK is also up-regulated, resulting in the elevation of BCAA concentrations and insulin resistance. In this application, we will test the central hypothesis that the highly related mitochondrial PDK and BDK are novel pharmacological targets for reducing glucose level and restoring insulin sensitivity in obesity and T2D.
The specific aims are: 1) to improve the potency and selectivity of novel PDK inhibitors developed in the PI's laboratory using structure-based design;2) to test the hypothesis that increased glucose oxidation and reduced lipogenesis occurs concurrently through PDK inhibitor augmented pyruvate flux in obesity and T2D;3) to test the hypothesis that increased BCAA oxidation ameliorates hyperglycemia and restores insulin sensitivity in T2D. The available novel PDK and BDK inhibitors and animal models including diet-induced obese mice, ob/ob mice and Zucker obese rats will be utilized in the proposed studies. A successful outcome of this investigation will provide the framework for developing new therapeutic approaches to the treatments of obesity and T2D.
Obesity has reached epidemic proportions in the United States and is strongly linked to type 2 diabetes. In this application, we will utilize small-molecue inhibitors to deactivate specific mitochondrial protein kinases thereby mitigating hyperglycemia and insulin resistance in animal models. A successful outcome of this research will provide the framework for developing more effective therapeutic approaches to obesity and type 2 diabetes.
|Wu, Cheng-Yang; Satapati, Santhosh; Gui, Wenjun et al. (2018) A novel inhibitor of pyruvate dehydrogenase kinase stimulates myocardial carbohydrate oxidation in diet-induced obesity. J Biol Chem 293:9604-9613|
|White, Phillip J; McGarrah, Robert W; Grimsrud, Paul A et al. (2018) The BCKDH Kinase and Phosphatase Integrate BCAA and Lipid Metabolism via Regulation of ATP-Citrate Lyase. Cell Metab 27:1281-1293.e7|
|Tso, Shih-Chia; Lou, Mingliang; Wu, Cheng-Yang et al. (2017) Development of Dihydroxyphenyl Sulfonylisoindoline Derivatives as Liver-Targeting Pyruvate Dehydrogenase Kinase Inhibitors. J Med Chem 60:1142-1150|
|Sun, Haipeng; Olson, Kristine C; Gao, Chen et al. (2016) Catabolic Defect of Branched-Chain Amino Acids Promotes Heart Failure. Circulation 133:2038-49|
|Scheuermann, Thomas H; Brautigam, Chad A (2015) High-precision, automated integration of multiple isothermal titration calorimetric thermograms: new features of NITPIC. Methods 76:87-98|
|Tso, Shih-Chia; Qi, Xiangbing; Gui, Wen-Jun et al. (2014) Structure-guided development of specific pyruvate dehydrogenase kinase inhibitors targeting the ATP-binding pocket. J Biol Chem 289:4432-43|
|Tso, Shih-Chia; Gui, Wen-Jun; Wu, Cheng-Yang et al. (2014) Benzothiophene carboxylate derivatives as novel allosteric inhibitors of branched-chain ?-ketoacid dehydrogenase kinase. J Biol Chem 289:20583-93|
|Kennerson, Marina L; Yiu, Eppie M; Chuang, David T et al. (2013) A new locus for X-linked dominant Charcot-Marie-Tooth disease (CMTX6) is caused by mutations in the pyruvate dehydrogenase kinase isoenzyme 3 (PDK3) gene. Hum Mol Genet 22:1404-16|
|Hsu, Jye-Lin; Chuang, Woei-Jer; Su, Ih-Jen et al. (2013) Zinc-dependent interaction between JAB1 and pre-S2 mutant large surface antigen of hepatitis B virus and its implications for viral hepatocarcinogenesis. J Virol 87:12675-84|
|Wynn, R Max; Li, Jun; Brautigam, Chad A et al. (2012) Structural and biochemical characterization of human mitochondrial branched-chain ?-ketoacid dehydrogenase phosphatase. J Biol Chem 287:9178-92|
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