[BIO Colloquium] Orphan Nuclear Receptor ERRgamma and Liver Metabolic Disease
  • Hueng-Sik Choi, Ph.D.(Cheonnam National University)
  • SLS Colloquia / Apr 9th 04:00pm / AMRB 113
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 (ERRγ) is a member of the NR3B subfamily of the nuclear receptor superfamily. To date, the target genes and physiological functions of ERRγ in the liver remain unclear. Here, we show that the hepatic expression of ERRγ is induced under fasting in normal mice and in diabetic mice that exhibit elevated gluconeogenesis. Transient transfection assays reveal that the overexpression of ERRγ increases the transactivity of PEPCK promoter in HepG2 cell line. Electrophoretic mobility shift assays (EMSAs) and chromatin immunoprecipitation (ChIP) assays demonstrate that ERRγ binds directly to both ERRE1 and ERRE2 on PEPCK promoter. Adenoviral-mediated expression of ERRγ 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 ERRγ with Ad-RNAi construct disrupts both PEPCK and G6Pase gene expression induced by Forskolin in rat primary hepatocyte. These results implicate ERRγ as a novel downstream mediator of cAMP axis and as a key regulator of hepatic gluconeogenesis under fasting state.