Characterization of Novel Peroxisome Proliferator-activated Receptor Coactivator-1 (PGC-1 ) Isoform in Human Liver

Department of Laboratory Medicine, Paracelsus Medical University, 5020 Salzburg, Austria.
Journal of Biological Chemistry (Impact Factor: 4.57). 12/2011; 286(50):42923-36. DOI: 10.1074/jbc.M111.227496
Source: PubMed


Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) is a transcriptional coactivator that contributes to the regulation of numerous transcriptional programs including the hepatic response to fasting. Mechanisms at transcriptional and post-transcriptional levels allow PGC-1α to support distinct biological pathways. Here we describe a novel human liver-specific PGC-1α transcript that results from alternative promoter usage and is induced by FOXO1 as well as glucocorticoids and cAMP-response element-binding protein signaling but is not present in other mammals. Hepatic tissue levels of novel and wild-type transcripts were similar but were only moderately associated (p < 0.003). Novel mRNA levels were associated with a polymorphism located in its promoter region, whereas wild-type transcript levels were not. Furthermore, hepatic PCK1 mRNA levels exhibited stronger associations with the novel than with the wild-type transcript levels. Except for a deletion of 127 amino acids at the N terminus, the protein, termed L-PGC-1α, is identical to PGC-1α. L-PGC-1α was localized in the nucleus and showed coactivation properties that overlap with those of PGC-1α. Collectively, our data support a role of L-PGC-1α in gluconeogenesis, but functional differences predicted from the altered structure suggest that L-PGC-1α may have arisen to adapt PGC-1α to more complex metabolic pathways in humans.

    • "However, another study in mouse skeletal muscle found only two previously described isoforms (PGC-1α-a and NT-PGC-1α-b mRNAs), as well as two additional isoforms (PGC-1α-2 and PGC-1α-3 mRNAs) with multiple splicing between exons (Ruas et al. 2012). Other tissue-specific promoters and isoforms have been described in human nervous tissue (Soyal et al. 2012) and liver (Felder et al. 2011). "
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