고려대학교 생명과학대학 생명과학부/ 대학원 분자생명과학과

Abstract

Glucose homeostasis is maintained by the balance between hepatic glucose production by the liver and glucose utilization by muscles and adipose tissue. Under fasting, gluconeogenesis is strongly stimulated by enhancing the transcription of gluconeogenic genes via the cAMP axis by glucagon but is inhibited by insulin under feeding. Dysregulation of glucose metabolism is associated with insulin resistance and diabetes. Estrogen receptor-related receptor gamma (ERRg)is a member of the NR3B subfamily of the nuclear receptor superfamily. To date, the target genes and physiological functions of ERRgin the liver remain unclear. Here, we show that the hepatic expression of ERRgis induced under fasting in normal mice and in diabetic mice that exhibit elevated gluconeogenesis. Transient transfection assays reveal that the overexpression of ERRgincreases the transactivity of PEPCK promoter in HepG2 cell line.Electrophoretic mobility shift assays (EMSAs) and chromatin immunoprecipitation (ChIP) assays demonstrate that ERRgbinds directly to both ERRE1 and ERRE2 on PEPCK promoter. Adenoviral-mediated expression of ERRg increases mRNA levels of key gluconeogenic genes, such as phosphoenolpyrubate carboxykinsae(PEPCK) and glucose-6-phosphatase(G6Pase) both in vitro and in vivo, and raises blood glucose levels. Conversely, knockdown of ERRgwith Ad-RNAi construct disrupts both PEPCK and G6Pase gene expression induced by Forskolin in rat primary hepatocyte. These results implicate ERRgas a novel downstream mediator of cAMP axis and as a key regulator of hepatic gluconeogenesis under fasting state.