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

Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha) 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-1 alpha to support distinct biological pathways. Here we describe a novel human liver-specific PGC-1 alpha 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 wildtype 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-PGC1 alpha, is identical to PGC-1 alpha. L-PGC-1 alpha was localized in the nucleus and showed coactivation properties that overlap with those of PGC-1 alpha. Collectively, our data support a role of L-PGC-1 alpha in gluconeogenesis, but functional differences predicted from the altered structure suggest that L-PGC-1 alpha may have arisen to adapt PGC-1 alpha to more complex metabolic pathways in humans.