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. 2008:2008:279531.
doi: 10.1155/2008/279531.

Cardiac PPARalpha Protein Expression is Constant as Alternate Nuclear Receptors and PGC-1 Coordinately Increase During the Postnatal Metabolic Transition

Norman E Buroker  1 , Xue-Han Ning, Michael Portman
Affiliations

Cardiac PPARalpha Protein Expression is Constant as Alternate Nuclear Receptors and PGC-1 Coordinately Increase During the Postnatal Metabolic Transition

Norman E Buroker et al. PPAR Res. 2008.

Abstract

Gene expression data obtained in mouse heart indicate that increased expression for the nuclear receptor, peroxisomal proliferator activated receptor alpha (PPARalpha), prompts the postnatal transition from predominantly carbohydrate to fatty acid oxidation preference. However, no phenotypic or proteomic data are available to confirm downstream signaling and metabolic transition in mice. We studied the hypothesis that shifts in nuclear receptor expression trigger the newborn metabolic switch in a newborn sheep. This species is well characterized with regards to developmental changes in substrate oxidative metabolism. Heart tissues from fetal (130 days gestation), newborn </=24 hours, and 30-day old lambs were evaluated for protein expression from multiple enzymes controlling oxidative metabolism as well as principal nuclear receptors and coactivators. Although muscle and liver type carnitine palmitoyl transferases I showed no significant changes to correspond to the metabolic transition, hexokinase II protein content showed a profound transient drop, and pyruvate dehydrogenase kinase steadily increased. PPARalpha showed no increases preceding or during the transition, while peroxisomal proliferator activated receptor gamma coactivator-1 (PGC-1) increased approximately 20-fold transiently in newborn heart in conjunction with significant increases in thyroid hormone receptor alpha1 and retinoid-activated receptor alpha. These data challenge the paradigm that increases in PPARalpha prompt the postnatal metabolic switch, and suggest that other nuclear receptors play a major role. As thyroid hormone (TH) modulates PGC-1 expression in sheep during development, these data further suggest that well-characterized perinatal TH surge in sheep contributes to this metabolic switch.

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Figures

Figure 1
Figure 1
Immunoblots and expression patterns for enzymes controlling substrate oxidation. Data is shown for left ventricle from three development periods (F, N, C) as defined in text. Abbreviations are carnitine palmitoyltransferase I (muscle isoform M-CPTI), carnitine palmitoyltransferase I (liver isoform L-CPTI), hexokinase 2 (HK2), and pyruvate dehydrogenase kinase 2 (PDK2). M-CPTI protein expression decreases occurred between N and C (*P<.01). L-CPTI protein expression differences decreased immediately after birth F (*P<.01) and continued to drop in C (+ P<0.001, versus N). HK2 protein expression exhibited a marked but transient decrease after birth N (*P<.05, versus F & C). PDK2 protein expression increased with significance noted in C compared to F and N (*P<.05, F & N).
Figure 2
Figure 2
Cytochrome c oxidase 3 expression serves a reporter for the mitochondrial genome (MTCO3; Cytochrome c oxidase polypeptide 3; E.C. 1.9.3.1). MTCO3 increased transiently in the newborn (**P<.01, versus F & C). Coordinate changes in protein content occurred for PGC-1α, implicated as a regulator of mitochondrial biogenesis.
Figure 3
Figure 3
Content for nuclear receptors peroxisome proliferator-activated receptor (PPARα), (b) retinoid X receptor alpha (RXRα), and thyroid hormone receptor (TRα 1) among three stages (F, N, C). Modest transient but significant elevations for RXRα and TRα 1 occurred in N compared to both F and C (*P<.01). PPARα expression did not change immediately after birth, but later decreased compared to F and N (*P<.01).
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