title: Peroxisome proliferator-activated receptor alpha (PPARalpha) influences substrate utilization for hepatic glucose production.
abstract: 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-(13)C(6)]glucose, and HGP, lactate, and glycerol turnover was estimated utilizing either [U-(13)C(3)]lactate or [2-(13)C]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-(13)C(3)]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-(13)C]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.
authors.affiliation: Department of Medicine, the Laboratory of Metabolomics, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
authors.forename: Gary
authors.initials: G
authors.lastname: Xiao
authors.forename: Chuck
authors.initials: C
authors.lastname: Trujillo
authors.forename: Vicky
authors.initials: V
authors.lastname: Chang
authors.forename: Lilia
authors.initials: L
authors.lastname: Blanco
authors.forename: Sean B
authors.initials: SB
authors.lastname: Joseph
authors.forename: Sara
authors.initials: S
authors.lastname: Bassilian
authors.forename: Mohammed F
authors.initials: MF
authors.lastname: Saad
authors.forename: Peter
authors.initials: P
authors.lastname: Tontonoz
authors.forename: W N Paul
authors.initials: WN
authors.lastname: Lee
authors.forename: Irwin J
authors.initials: IJ
authors.lastname: Kurland
mesh_terms: D000818:Animals; D001483:Base Sequence; D001786:Blood Glucose / Q000378:metabolism; D002247:Carbon Isotopes; D017931:DNA Primers; D005215:Fasting; D015971:Gene Expression Regulation, Enzymologic; D005943:Gluconeogenesis / Q000502:physiology*; D005947:Glucose / Q000378:metabolism; D005990:Glycerol / Q000008:administration & dosage / Q000378:metabolism; D006706:Homeostasis; D007328:Insulin / Q000097:blood; D019344:Lactic Acid / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D011770:Pyruvate Kinase / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D001786:Blood Glucose; D002247:Carbon Isotopes; D017931:DNA Primers; D007328:Insulin; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D019344:Lactic Acid; D011770:Pyruvate Kinase; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D005947:Glucose; D005990:Glycerol