Peroxisome proliferator-activated receptor α (PPARα) influences

Substrate utilization for hepatic glucose production

Jun Xu, Gary Xiao, Chuck Tirujillo, Vicky Chang, Lilia Blanco, Sean B. Joseph, Sara Bassilian, Mohammed F. Saad, Peter Tontonoz, W. N Paul Lee, Irwin J. Kurland

Research output: Contribution to journalArticle

93 Citations (Scopus)

Abstract

The hypoglycemia seen in the fasting PPARα null mouse is thought to be due to impaired liver fatty acid β-oxidation. The etiology of hypoglycemia in the PPARα 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 PPARα 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 PPARα null mice than in WT by 37% (p < 0.01). However, recycling of glucose carbon from lactate back to glucose was lower in the PPARa 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 PPARa 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 PPARα null mice. The increased HGP from glycerol was not suppressed in the fed state. While little change was evident for phosphoenolpyruvate carboxykinase (PEPCX) expression, pyruvate kinase expression was decreased 16-fold in fasted PPARα 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 PPARα null mice than in controls. In conclusion, PPARα 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.

Original languageEnglish (US)
Pages (from-to)50237-50244
Number of pages8
JournalJournal of Biological Chemistry
Volume277
Issue number52
DOIs
StatePublished - Dec 27 2002
Externally publishedYes

Fingerprint

Peroxisome Proliferator-Activated Receptors
Lactic Acid
Glucose
Glycerol
Liver
Substrates
Fluxes
Hypoglycemia
Recycling
Carbon
Trioses
Phosphoenolpyruvate
Pyruvate Kinase
Metabolic Networks and Pathways
Pyruvic Acid
Inbred C57BL Mouse
Isotopes
Blood Glucose
Fasting

ASJC Scopus subject areas

  • Biochemistry

Cite this

Peroxisome proliferator-activated receptor α (PPARα) influences : Substrate utilization for hepatic glucose production. / Xu, Jun; Xiao, Gary; Tirujillo, Chuck; Chang, Vicky; Blanco, Lilia; Joseph, Sean B.; Bassilian, Sara; Saad, Mohammed F.; Tontonoz, Peter; Lee, W. N Paul; Kurland, Irwin J.

In: Journal of Biological Chemistry, Vol. 277, No. 52, 27.12.2002, p. 50237-50244.

Research output: Contribution to journalArticle

Xu, J, Xiao, G, Tirujillo, C, Chang, V, Blanco, L, Joseph, SB, Bassilian, S, Saad, MF, Tontonoz, P, Lee, WNP & Kurland, IJ 2002, 'Peroxisome proliferator-activated receptor α (PPARα) influences: Substrate utilization for hepatic glucose production', Journal of Biological Chemistry, vol. 277, no. 52, pp. 50237-50244. https://doi.org/10.1074/jbc.M201208200
Xu, Jun ; Xiao, Gary ; Tirujillo, Chuck ; Chang, Vicky ; Blanco, Lilia ; Joseph, Sean B. ; Bassilian, Sara ; Saad, Mohammed F. ; Tontonoz, Peter ; Lee, W. N Paul ; Kurland, Irwin J. / Peroxisome proliferator-activated receptor α (PPARα) influences : Substrate utilization for hepatic glucose production. In: Journal of Biological Chemistry. 2002 ; Vol. 277, No. 52. pp. 50237-50244.
@article{e7c62c5bf17046be9ced9e08df97f44a,
title = "Peroxisome proliferator-activated receptor α (PPARα) influences: Substrate utilization for hepatic glucose production",
abstract = "The hypoglycemia seen in the fasting PPARα null mouse is thought to be due to impaired liver fatty acid β-oxidation. The etiology of hypoglycemia in the PPARα 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 PPARα 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 PPARα null mice than in WT by 37{\%} (p < 0.01). However, recycling of glucose carbon from lactate back to glucose was lower in the PPARa 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 PPARa 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 PPARα null mice. The increased HGP from glycerol was not suppressed in the fed state. While little change was evident for phosphoenolpyruvate carboxykinase (PEPCX) expression, pyruvate kinase expression was decreased 16-fold in fasted PPARα 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 PPARα null mice than in controls. In conclusion, PPARα 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.",
author = "Jun Xu and Gary Xiao and Chuck Tirujillo and Vicky Chang and Lilia Blanco and Joseph, {Sean B.} and Sara Bassilian and Saad, {Mohammed F.} and Peter Tontonoz and Lee, {W. N Paul} and Kurland, {Irwin J.}",
year = "2002",
month = "12",
day = "27",
doi = "10.1074/jbc.M201208200",
language = "English (US)",
volume = "277",
pages = "50237--50244",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "52",

}

TY - JOUR

T1 - Peroxisome proliferator-activated receptor α (PPARα) influences

T2 - Substrate utilization for hepatic glucose production

AU - Xu, Jun

AU - Xiao, Gary

AU - Tirujillo, Chuck

AU - Chang, Vicky

AU - Blanco, Lilia

AU - Joseph, Sean B.

AU - Bassilian, Sara

AU - Saad, Mohammed F.

AU - Tontonoz, Peter

AU - Lee, W. N Paul

AU - Kurland, Irwin J.

PY - 2002/12/27

Y1 - 2002/12/27

N2 - The hypoglycemia seen in the fasting PPARα null mouse is thought to be due to impaired liver fatty acid β-oxidation. The etiology of hypoglycemia in the PPARα 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 PPARα 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 PPARα null mice than in WT by 37% (p < 0.01). However, recycling of glucose carbon from lactate back to glucose was lower in the PPARa 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 PPARa 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 PPARα null mice. The increased HGP from glycerol was not suppressed in the fed state. While little change was evident for phosphoenolpyruvate carboxykinase (PEPCX) expression, pyruvate kinase expression was decreased 16-fold in fasted PPARα 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 PPARα null mice than in controls. In conclusion, PPARα 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.

AB - The hypoglycemia seen in the fasting PPARα null mouse is thought to be due to impaired liver fatty acid β-oxidation. The etiology of hypoglycemia in the PPARα 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 PPARα 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 PPARα null mice than in WT by 37% (p < 0.01). However, recycling of glucose carbon from lactate back to glucose was lower in the PPARa 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 PPARa 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 PPARα null mice. The increased HGP from glycerol was not suppressed in the fed state. While little change was evident for phosphoenolpyruvate carboxykinase (PEPCX) expression, pyruvate kinase expression was decreased 16-fold in fasted PPARα 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 PPARα null mice than in controls. In conclusion, PPARα 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.

UR - http://www.scopus.com/inward/record.url?scp=0037184921&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037184921&partnerID=8YFLogxK

U2 - 10.1074/jbc.M201208200

DO - 10.1074/jbc.M201208200

M3 - Article

VL - 277

SP - 50237

EP - 50244

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 52

ER -