Characterization of novel peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) isoform in human liver.
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.
Pubmed ID: 22009745 RIS Download
8-Bromo Cyclic Adenosine Monophosphate | Animals | Blotting, Northern | Chromatin Immunoprecipitation | Dexamethasone | Female | Gene Expression | Genotype | Heat-Shock Proteins | Hep G2 Cells | Humans | Immunoblotting | In Vitro Techniques | Liver | Mice | Microscopy, Fluorescence | Molecular Sequence Data | Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha | Protein Isoforms | RNA, Messenger | Rats | Transcription Factors