EFFECTS OF LIVER SPECIFIC KNOCKOUT OF PEPCK ON GLUCOSE METABOLISM

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Commonly, PEPCK is considered the most important of the control points for gluconeogenesis. However, this fundamental dogma is difficult to test because it would require the combination of in vivo control of enzyme expression and the ability to measure flux through the enzymes of intact tissue. Magnuson and co-workers have generated mice with PEPCK expression ranging from 0-100% of normal mice by using an allelogenic Cre/loxP strategy. We are collaborating with Dr. Burgess in the Advanced Imaging Center to measure fluxes in the intact liver of mice generated at Vanderbilt with graded levels of PEPCK expression. This arrangement offers a unique and important opportunity to understand the control of PEPCK in the intact liver (and eventually kidney) on gluconeogenesis and other peripheral pathways such as fatty acid oxidation. The connection between PEPCK and metabolic pathways besides gluconeogenesis is highlighted by the observation that inhibiting PEPCK expression induces hepatic steatosis and causes large increases in certain intermediate pool sizes. The development of hepatic steatosis in the PEPCK KO mouse seems paradoxical in light of the fact that the enzymes of ?-oxidation are actually up-regulated. Measuring flux through these metabolic pathways of the liver and kidney of these mice will help us better understand the position of control this enzyme occupies in the gluconeogenic pathway.