title: Transcriptional coactivator NT-PGC-1α promotes gluconeogenic gene expression and enhances hepatic gluconeogenesis.
abstract: The transcriptional coactivator PGC-1α plays a central role in hepatic gluconeogenesis. We previously reported that alternative splicing of the PGC-1α gene produces an additional transcript encoding the truncated protein NT-PGC-1α NT-PGC-1α is co-expressed with PGC-1α and highly induced by fasting in the liver. NT-PGC-1α regulates tissue-specific metabolism, but its role in the liver has not been investigated. Thus, the objective of this study was to determine the role of hepatic NT-PGC-1α in the regulation of gluconeogenesis. Adenovirus-mediated expression of NT-PGC-1α in primary hepatocytes strongly stimulated the expression of key gluconeogenic enzyme genes (PEPCK and G6Pase), leading to increased glucose production. To further understand NT-PGC-1α function in hepatic gluconeogenesis in vivo, we took advantage of a previously reported FL-PGC-1α-/-mouse line that lacks full-length PGC-1α (FL-PGC-1α) but retains a slightly shorter and functionally equivalent form of NT-PGC-1α (NT-PGC-1α254). In FL-PGC-1α-/-mice, NT-PGC-1α254was induced by fasting in the liver and recruited to the promoters of PEPCK and G6Pase genes. The enrichment of NT-PGC-1α254at the promoters was closely associated with fasting-induced increase in PEPCK and G6Pase gene expression and efficient production of glucose from pyruvate during a pyruvate tolerance test in FL-PGC-1α-/-mice. Moreover, FL-PGC-1α-/-primary hepatocytes showed a significant increase in gluconeogenic gene expression and glucose production after treatment with dexamethasone and forskolin, suggesting that NT-PGC-1α254is sufficient to stimulate the gluconeogenic program in the absence of FL-PGC-1α Collectively, our findings highlight the role of hepatic NT-PGC-1α in stimulating gluconeogenic gene expression and glucose production.
authors: Laboratory of Gene Regulation and Metabolism, Pennington Biomedical Research Center, Baton Rouge, Louisiana jisuk.chang@pbrc.edu.
authors: Ji Suk
authors: JS
authors: Chang
authors: Laboratory of Gene Regulation and Metabolism, Pennington Biomedical Research Center, Baton Rouge, Louisiana.
authors: Hee-Jin
authors: HJ
authors: Jun
authors: Laboratory of Gene Regulation and Metabolism, Pennington Biomedical Research Center, Baton Rouge, Louisiana.
authors: Minsung
authors: M
authors: Park
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D005943:Gluconeogenesis / Q000235:genetics*; D005947:Glucose / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors; D005947:Glucose
keywords: Diabetes; NT‐PGC‐1alpha; PGC‐1alpha; Ppargc1a protein; hepatic gluconeogenesis; obesity