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Originally published In Press as doi:10.1074/jbc.M201208200 on August 9, 2002

J. Biol. Chem., Vol. 277, Issue 52, 50237-50244, December 27, 2002
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Peroxisome Proliferator-activated Receptor alpha  (PPARalpha ) Influences Substrate Utilization for Hepatic Glucose Production*

Jun XuDagger §, Gary XiaoDagger §, Chuck TrujilloDagger §, Vicky ChangDagger §, Lilia BlancoDagger §, Sean B. Joseph||, Sara Bassilian**, Mohammed F. Saad§, Peter Tontonoz||Dagger Dagger §§, W. N. Paul Lee**, and Irwin J. KurlandDagger §Dagger Dagger ¶¶

From the § Department of Medicine, the Dagger  Laboratory of Metabolomics, the  Department of Biological Chemistry, the || Department of Pathology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, Dagger Dagger  Molecular Biology Institute, UCLA, Los Angeles, California 90095, and the ** Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California 90502

The hypoglycemia seen in the fasting PPARalpha null mouse is thought to be due to impaired liver fatty acid beta -oxidation. The etiology of hypoglycemia in the PPARalpha null mouse was determined via stable isotope studies. Glucose, lactate, and glycerol flux was assessed in the fasted and fed states in 4-month-old PPARalpha null mice and in C57BL/6 WT maintained on standard chow using a new protocol for flux assessment in the fasted and fed states. Hepatic glucose production (HGP) and glucose carbon recycling were estimated using [U-13C6]glucose, and HGP, lactate, and glycerol turnover was estimated utilizing either [U-13C3]lactate or [2-13C]glycerol infused subcutaneously via Alza miniosmotic pumps. At the end of a 17-h fast, HGP was higher in the PPARalpha null mice than in WT by 37% (p < 0.01). However, recycling of glucose carbon from lactate back to glucose was lower in the PPARalpha null than in WT (39% versus 51%, p < 0.02). The lack of conversion of lactate to glucose was confirmed using an [U-13C3]lactate infusion. In the fasted state, HGP from lactate and lactate production were decreased by 65 and 55%, respectively (p < 0.05) in PPARalpha null mice. In contrast, when [2-13C]glycerol was infused, glycerol production and HGP from glycerol increased by 80 and 250%, respectively (p < 0.01), in the fasted state of PPARalpha null mice. The increased HGP from glycerol was not suppressed in the fed state. While little change was evident for phosphoenolpyruvate carboxykinase (PEPCK) expression, pyruvate kinase expression was decreased 16-fold in fasted PPARalpha null mice as compared with the wild-type control. The fasted and fed insulin levels were comparable, but blood glucose levels were lower in the PPARalpha null mice than in controls. In conclusion, PPARalpha receptor function creates a setpoint for a metabolic network that regulates the rate and route of HGP in the fasted and fed states, in part, by controlling the flux of glycerol and lactate between the triose-phosphate and pyruvate/lactate pools.

* This work was supported by a grant from the American Diabetes Association (to I. J. K.) and Grants DK56090-A1 (to W. N. P. L.) and HL66088 (to P. T.). The GC/MS Facility is supported by United States Public Health Service Grant P01-CA42710 to the UCLA Clinical Nutrition Research Unit, Stable Isotope Core and Grant M01-RR00425 to the General Clinical Research Center.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§§ Assistant investigator of the Howard Hughes Medical Institute at the University of California, Los Angeles, CA 90095.

¶¶ To whom correspondence should be addressed. Tel.: 818-634-6953; Fax: 310-825-8534; E-mail address: irwinjk@earthlink.net.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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