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J. Biol. Chem., Vol. 279, Issue 47, 48941-48949, November 19, 2004

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Impaired Tricarboxylic Acid Cycle Activity in Mouse Livers Lacking Cytosolic Phosphoenolpyruvate Carboxykinase^*

Shawn C. Burgess, Natasha Hausler, Matthew Merritt, F. Mark H. Jeffrey, Charles Storey, Angela Milde, Seena Koshy¶, Jill Lindner||, Mark A. Magnuson||, Craig R. Malloy**, and A. Dean Sherry¶

From the The Mary Nell and Ralph B. Rogers Magnetic Resonance Center, Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas 75235-9085, the ^¶Department of Chemistry, University of Texas, Dallas, Texas 75083-0688, the ^||Department of Molecular Physiology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0615, and the ^**Department of Internal Medicine, Veterans Affairs North Texas Health Care System, University of Texas Southwestern Medical Center, Dallas, Texas 75235-9085

Liver-specific phosphoenolpyruvate carboxykinase (PEPCK) null mice, when fasted, maintain normal whole body glucose kinetics but develop dramatic hepatic steatosis. To identify the abnormalities of hepatic energy generation that lead to steatosis during fasting, we studied metabolic fluxes in livers lacking hepatic cytosolic PEPCK by NMR using ²H and ¹³C tracers. After a 4-h fast, glucose production from glycogenolysis and conversion of glycerol to glucose remains normal, whereas gluconeogenesis from tricarboxylic acid (TCA) cycle intermediates was nearly absent. Upon an extended 24-h fast, livers that lack PEPCK exhibit both 2-fold lower glucose production and oxygen consumption, compared with the controls, with all glucose production being derived only from glycerol. The mitochondrial reduction-oxidation (red-ox) state, as indicated by the NADH/NAD⁺ ratio, is 5-fold higher, and hepatic TCA cycle intermediate concentrations are dramatically increased in the PEPCK null livers. Consistent with this, flux through the TCA cycle and pyruvate cycling pathways is 10- and 40-fold lower, respectively. Disruption of hepatic cataplerosis due to loss of PEPCK leads to the accumulation of TCA cycle intermediates and a nearly complete blockage of gluconeogenesis from amino acids and lactate (an energy demanding process) but intact gluconeogenesis from glycerol (which contributes to net NADH production). Inhibition of the TCA cycle and fatty acid oxidation due to increased TCA cycle intermediate concentrations and reduced mitochondrial red-ox state lead to the development of steatosis.

Received for publication, June 24, 2004 , and in revised form, August 30, 2004.

^* This work was supported in part by National Institutes of Health Grants RR02584, U24-DK59632, and HL-34557 and a grant from the American Diabetes Association (to M. A. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: the University of Texas Southwestern Medical Center, Mary Nell and Ralph B. Rogers Magnetic Resonance Center, 5801 Forest Park Rd., Dallas, TX 75235-9085. Tel.: 214-648-5893; Fax: 214-648-5881; E-mail: shawn.burgess{at}utsouthwestern.edu.

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