Volume 29, Issue S1 884.12
Biochemistry and Molecular Biology
Free Access

Regulation of Hepatic Gluconeogenesis by NT-PGC-1α, the Short Isoform of PGC-1α

Ji Suk Chang

Ji Suk Chang

Gene Regulation and Metabolism Pennington Biomedical Research Center, Baton Rouge, LA, United States

Search for more papers by this author
Hee-Jin Jun

Hee-Jin Jun

Gene Regulation and Metabolism Pennington Biomedical Research Center, Baton Rouge, LA, United States

Search for more papers by this author

Abstract

Hepatic gluconeogenesis is critical for maintaining blood glucose homeostasis; but excessive hepatic gluconeogenesis is a major contributor to hyperglycemia in type 2 diabetes. The transcriptional coactivator PGC-1α plays a central role in regulating hepatic gluconeogenesis by transcriptional induction of key gluconeogenic enzymes (PEPCK and G6Pase) in response to nutrient deprivation. An aberrant elevation of PGC-1α gene expression in the diabetic liver stimulates hepatic glucose production, thus contributing to the development of hyperglycemia in type 2 diabetes. In the current study, we have found that an N-terminal isoform of PGC-1α (designated NT-PGC-1α), which is generated by alternative splicing of the PGC-1α gene, is co-expressed with PGC-1α in the liver and highly induced in response to cAMP and glucocorticoid signaling in fasted mice. Forced expression of NT-PGC-1α in primary hepatocytes robustly drives the expression of PEPCK and G6Pase and increases glucose production. In agreement with this finding, NT-PGC-1α is sufficient to activate the entire gluconeogenic program in mice deficient in PGC-1α, thus resulting in normal blood glucose levels during prolonged fasting. Mechanistically, fasting-induced NT-PGC-1α interacts with HNF4α and is recruited to the promoters of PEPCK and G6Pase to stimulate gluconeogenic gene expression. Together, these data clearly demonstrate that NT-PGC-1α plays a crucial role, along with PGC-1α, in the regulation of hepatic gluconeogenesis. Moreover, elevated expression of hepatic NT-PGC-1α in diabetic ob/ob mice indicates its implication in elevated hepatic glucose production in type 2 diabetes. Grant funding source: COBRE (NIH8 P20-GM103528) center grant from the NIH.