Impairments of hepatic gluconeogenesis and ketogenesis in PPARα-deficient neonatal mice

American Journal of Physiology. Endocrinology and Metabolism
David G CotterPeter A Crawford

Abstract

Peroxisome proliferator activated receptor-α (PPARα) is a master transcriptional regulator of hepatic metabolism and mediates the adaptive response to fasting. Here, we demonstrate the roles for PPARα 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. PPARα-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 PPARα 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 PPARα-KO neonates. Relative hypoketonemia in newborn PPARα-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 mitochon...Continue Reading

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Citations

Oct 28, 2014·The Journal of Clinical Investigation·David G CotterPeter A Crawford
Nov 25, 2016·American Journal of Physiology. Heart and Circulatory Physiology·Stephen W StandageAaron K Olson
Nov 9, 2018·Diabetes, Obesity & Metabolism·Jin Hee KimYong-Ho Lee
Jun 7, 2019·JPEN. Journal of Parenteral and Enteral Nutrition·Bruce R Bistrian
Apr 18, 2020·Scientific Reports·Marion RégnierAlexandra Montagner
Oct 11, 2020·The Journal of Biological Chemistry·Yann DeleyeRéjane Paumelle
Jan 21, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Tomokazu OhishiMamoru Isemura
Nov 2, 2019·Biochimica Et Biophysica Acta. Molecular Basis of Disease·Nikica TomašićVineta Fellman
Jan 18, 2021·The Journal of Biological Chemistry·Yann DeleyeRéjane Paumelle
Aug 6, 2021·Expert Opinion on Pharmacotherapy·Marc S Rendell

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