The Developmental Regulation of Peroxisome Proliferator-Activated Receptor-γ Coactivator-1α Expression in the Liver Is Partially Dissociated from the Control of Gluconeogenesis and Lipid Catabolism

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Abstract
The developmental regulation of peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) gene expression was studied in mice and compared with that of marker genes of liver energy metabolism. The PGC-1alpha gene was highly expressed in fetal liver compared with that in adults and remained high in neonatal liver. The regulation of PGC-1alpha gene expression during the fetal and early neonatal periods was dissociated from that of gluconeogenic genes, i.e. the phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) genes. Only under the effects of starvation was PGC-1alpha gene expression induced in parallel to phosphoenolpyruvate carboxykinase and G6Pase mRNAs during the perinatal period. Furthermore, the PGC-1alpha gene was not regulated as part of the developmental program of gene expression associated with the maturation of hepatic gluconeogenesis, as revealed by the impaired PEPCK and G6Pase gene expression but unaltered PGC-1alpha mRNA levels in CCAAT/enhancer-binding protein-alpha-null fetus and neonates. Regulation of the PGC-1alpha gene and that of mitochondrial 3-hydroxy-3-methyl-glutaryl-coenzyme A synthase, acyl-coenzyme A oxidase, and long-chain acyl-coenzyme dehydrogenase, marker genes of lipid catabolism, were dissociated in fetuses and neonates. The expression of lipid catabolism genes was down-regulated in fasted neonates, whereas PGC-1alpha was oppositely regulated. The independent regulation of PGC-1alpha and lipid catabolism genes was also found in peroxisome proliferator-activated receptor-alpha-null neonates, in which PGC-1alpha mRNA levels were unaffected whereas gene expression for 3-hydroxy-3-methyl-glutaryl-coenzyme A synthase and acyl-coenzyme A oxidase was impaired. Thus, regulation of the PGC-1alpha gene is partially dissociated from the patterns of regulation of hepatic genes encoding enzymes involved in gluconeogenesis and lipid catabolism during fetal ontogeny and in response to the initiation of lactation.