PMID- 24865983
OWN - NLM
STAT- MEDLINE
DCOM- 20140923
LR  - 20211021
IS  - 1522-1555 (Electronic)
IS  - 0193-1849 (Print)
IS  - 0193-1849 (Linking)
VI  - 307
IP  - 2
DP  - 2014 Jul 15
TI  - Impairments of hepatic gluconeogenesis and ketogenesis in PPARalpha-deficient 
      neonatal mice.
PG  - E176-85
LID - 10.1152/ajpendo.00087.2014 [doi]
AB  - Peroxisome proliferator activated receptor-alpha (PPARalpha) is a master transcriptional 
      regulator of hepatic metabolism and mediates the adaptive response to fasting. 
      Here, we demonstrate the roles for PPARalpha in hepatic metabolic adaptations to 
      birth. Like fasting, nutrient supply is abruptly altered at birth when a 
      transplacental source of carbohydrates is replaced by a high-fat, 
      low-carbohydrate milk diet. PPARalpha-knockout (KO) neonatal mice exhibit relative 
      hypoglycemia due to impaired conversion of glycerol to glucose. Although hepatic 
      expression of fatty acyl-CoA dehydrogenases is imparied in PPARalpha neonates, these 
      animals exhibit normal blood acylcarnitine profiles. Furthermore, quantitative 
      metabolic fate mapping of the medium-chain fatty acid [(13)C]octanoate in 
      neonatal mouse livers revealed normal contribution of this fatty acid to the 
      hepatic TCA cycle. Interestingly, octanoate-derived carbon labeled glucose 
      uniquely in livers of PPARalpha-KO neonates. Relative hypoketonemia in newborn 
      PPARalpha-KO animals could be mechanistically linked to a 50% decrease in de novo 
      hepatic ketogenesis from labeled octanoate. Decreased ketogenesis was associated 
      with diminished mRNA and protein abundance of the fate-committing ketogenic 
      enzyme mitochondrial 3-hydroxymethylglutaryl-CoA synthase (HMGCS2) and decreased 
      protein abundance of the ketogenic enzyme beta-hydroxybutyrate dehydrogenase 1 
      (BDH1). Finally, hepatic triglyceride and free fatty acid concentrations were 
      increased 6.9- and 2.7-fold, respectively, in suckling PPARalpha-KO neonates. 
      Together, these findings indicate a primary defect of gluconeogenesis from 
      glycerol and an important role for PPARalpha-dependent ketogenesis in the disposal of 
      hepatic fatty acids during the neonatal period.
CI  - Copyright (c) 2014 the American Physiological Society.
FAU - Cotter, David G
AU  - Cotter DG
AD  - Department of Medicine, Center for Cardiovascular Research, and Departments of 
      Pediatrics.
FAU - Ercal, Baris
AU  - Ercal B
AD  - Department of Medicine, Center for Cardiovascular Research, and.
FAU - d'Avignon, D Andre
AU  - d'Avignon DA
AD  - Chemistry, and.
FAU - Dietzen, Dennis J
AU  - Dietzen DJ
AD  - Departments of Pediatrics.
FAU - Crawford, Peter A
AU  - Crawford PA
AD  - Department of Medicine, Center for Cardiovascular Research, and Genetics, 
      Washington University, St. Louis, Missouri pcrawford@wustl.edu.
LA  - eng
GR  - R01 DK091538/DK/NIDDK NIH HHS/United States
GR  - HL-007873/HL/NHLBI NIH HHS/United States
GR  - DK-052574/DK/NIDDK NIH HHS/United States
GR  - P30 DK056341/DK/NIDDK NIH HHS/United States
GR  - DK-091538/DK/NIDDK NIH HHS/United States
GR  - DK-020579/DK/NIDDK NIH HHS/United States
GR  - DK-056341/DK/NIDDK NIH HHS/United States
GR  - P30 DK020579/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20140527
PL  - United States
TA  - Am J Physiol Endocrinol Metab
JT  - American journal of physiology. Endocrinology and metabolism
JID - 100901226
RN  - 0 (Fatty Acids)
RN  - 0 (Ketone Bodies)
RN  - 0 (PPAR alpha)
RN  - PDC6A3C0OX (Glycerol)
SB  - IM
MH  - Animals
MH  - Animals, Newborn
MH  - Fatty Acids/metabolism
MH  - Gluconeogenesis/*genetics
MH  - Glycerol/metabolism
MH  - Hypoglycemia/genetics/metabolism
MH  - Ketone Bodies/*metabolism
MH  - Liver/*metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Oxidation-Reduction
MH  - PPAR alpha/*genetics
PMC - PMC4101633
OTO - NOTNLM
OT  - 3-hydroxymethylglutaryl-CoA synthase
OT  - glucose homeostasis
OT  - ketone body metabolism
OT  - metabolic adaptation to birth
OT  - nuclear magnetic resonance substrate fate mapping
OT  - peroxisome proliferator-activated receptor-alpha
EDAT- 2014/05/29 06:00
MHDA- 2014/09/24 06:00
PMCR- 2015/07/15
CRDT- 2014/05/29 06:00
PHST- 2014/05/29 06:00 [entrez]
PHST- 2014/05/29 06:00 [pubmed]
PHST- 2014/09/24 06:00 [medline]
PHST- 2015/07/15 00:00 [pmc-release]
AID - ajpendo.00087.2014 [pii]
AID - E-00087-2014 [pii]
AID - 10.1152/ajpendo.00087.2014 [doi]
PST - ppublish
SO  - Am J Physiol Endocrinol Metab. 2014 Jul 15;307(2):E176-85. doi: 
      10.1152/ajpendo.00087.2014. Epub 2014 May 27.