Abnormal liver carbohydrate and fat metabolism contribute to poor glucose and lipid homeostasis in a variety of metabolic diseases. For this reason, factors that regulate these metabolic pathways in the liver have been intensely studied, yet remain incompletely understood. Commonly, the expression of gluconeogenic enzymes, in particular phosphoenolpyruvate carboxykinase (PEPCK), are thought to control the rate of gluconeogenesis;however, how flux through these pathways change in response to enzyme expression (i.e. control strength) remains poorly understood. Our work demonstrates that in mice with graded levels of PEPCK expression, PEPCK control strength is weak, implying that other factors coordinate control of gluconeogenesis. One of these factors is the rate of hepatic energy production via fat oxidation. For instance, exposure of liver to high levels of fatty acids results in increased gluconeogenesis, and more recently, molecular factors have been identified that coordinate the enzymes of gluconeogenesis and fat oxidation in parallel. We've found that the rate of hepatic TCA cycle flux, a pathway intimately linked to hepatic energy production, correlates more strongly with flux through PEPCK than PEPCK enzyme expression itself. To continue our studies of these pathways we will measure metabolic fluxes in liver in response to altered expression of the gluconeogenic enzymes pyruvate carboxylase (PC) and PEPCK to determine their capacity to influence the rate of gluconeogenesis. Finally, since elevated fat delivery to liver is known to increase gluconeogenesis, and presumably flux through PC and PEPCK, we will also measure hepatic fluxes in response to altered fat availability. These studies will be performed using a multidisciplinary approach comprised of gene altered models, isolated organ preparations and rodent micro-surgery. Nuclear magnetic resonance (NMR) isotopomer analysis will be used to measure metabolic fluxes and these techniques will be corroborated by simultaneous hepatic mass balance determinations. Aberrant fluxes through metabolic pathways of the liver participate in the morbidity of numerous metabolic diseases. Work funded by this grant will substantially enhance our understanding of how metabolic pathways in the liver, specifically gluconeogenesis and fat oxidation, respond to changes in enzyme or substrate concentration. Ultimately, this knowledge is critical for development and interpretation of molecular or pharmacological interventions that modulate these pathways, either by design or happenstance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK078184-02
Application #
7558551
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Laughlin, Maren R
Project Start
2008-02-01
Project End
2012-11-30
Budget Start
2008-12-01
Budget End
2009-11-30
Support Year
2
Fiscal Year
2009
Total Cost
$314,000
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
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
Potts, Austin; Uchida, Aki; Deja, Stanislaw et al. (2018) Cytosolic phosphoenolpyruvate carboxykinase as a cataplerotic pathway in the small intestine. Am J Physiol Gastrointest Liver Physiol 315:G249-G258
Lan, Tian; Morgan, Donald A; Rahmouni, Kamal et al. (2017) FGF19, FGF21, and an FGFR1/?-Klotho-Activating Antibody Act on the Nervous System to Regulate Body Weight and Glycemia. Cell Metab 26:709-718.e3
Ragavan, Mukundan; Kirpich, Alexander; Fu, Xiaorong et al. (2017) A comprehensive analysis of myocardial substrate preference emphasizes the need for a synchronized fluxomic/metabolomic research design. Am J Physiol Heart Circ Physiol 312:H1215-H1223
Silvers, Molly A; Deja, Stanislaw; Singh, Naveen et al. (2017) The NQO1 bioactivatable drug, ?-lapachone, alters the redox state of NQO1+ pancreatic cancer cells, causing perturbation in central carbon metabolism. J Biol Chem 292:18203-18216
Kim, Chai-Wan; Addy, Carol; Kusunoki, Jun et al. (2017) Acetyl CoA Carboxylase Inhibition Reduces Hepatic Steatosis but Elevates Plasma Triglycerides in Mice and Humans: A Bedside to Bench Investigation. Cell Metab 26:394-406.e6
Morris, E Matthew; McCoin, Colin S; Allen, Julie A et al. (2017) Aerobic capacity mediates susceptibility for the transition from steatosis to steatohepatitis. J Physiol 595:4909-4926
Rauckhorst, Adam J; Gray, Lawrence R; Sheldon, Ryan D et al. (2017) The mitochondrial pyruvate carrier mediates high fat diet-induced increases in hepatic TCA cycle capacity. Mol Metab 6:1468-1479
Morris, E Matthew; Meers, Grace M E; Koch, Lauren G et al. (2016) Aerobic capacity and hepatic mitochondrial lipid oxidation alters susceptibility for chronic high-fat diet-induced hepatic steatosis. Am J Physiol Endocrinol Metab 311:E749-E760
Kucejova, Blanka; Duarte, Joao; Satapati, Santhosh et al. (2016) Hepatic mTORC1 Opposes Impaired Insulin Action to Control Mitochondrial Metabolism in Obesity. Cell Rep 16:508-519

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