title: Ginsenoside Rg2 induces orphan nuclear receptor SHP gene expression and inactivates GSK3β via AMP-activated protein kinase to inhibit hepatic glucose production in HepG2 cells.
abstract: Panax ginseng is known to have anti-diabetic activity, but the active ingredients have not been fully explored yet. Here, we test whether ginsenoside Rg2 has an inhibitory effect on hepatic glucose production and determine its mechanism of action. Rg2 significantly inhibits hepatic glucose production and induces phosphorylations of liver kinase B1 (LKB1), AMP-activated protein kinase (AMPK) and glycogen synthase kinase 3β (GSK3β) in time- and concentration-dependent manners in human HepG2 hepatoma cells, and these effects were abolished in the presence of compound C, a selective AMPK inhibitor. In addition, phosphorylated form of cAMP-response element-binding protein (CREB), a key transcription factor for hepatic gluconeogenesis, was decreased in time- and concentration-dependent manners. Next, gene expression of orphan nuclear receptor small heterodimer partner (SHP) was also examined. Rg2 markedly enhanced the gene expression of SHP and its direct interaction with CREB, which results in disruption of CREB·CRTC2 complex. Consequently, expressions of relevant genes such as peroxisome proliferation-activated receptor γ coactivator-1α (PGC-1α), phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) were all significantly suppressed and these effects were also reversed in the presence of compound C. In conclusion, our results propose that ginsenoside Rg2 suppresses the hepatic glucose production via AMPK-induced phosphorylation of GSK3β and induction of SHP gene expression. Further studies are warranted to elucidate a therapeutic potential of Rg2 for type 2 diabetic patients.
authors: Department of Pharmacology and Clinical Pharmacy, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea.
authors: Hai-Dan
authors: HD
authors: Yuan
authors: Do Yeon
authors: DY
authors: Kim
authors: Hai-Yan
authors: HY
authors: Quan
authors: Su Jung
authors: SJ
authors: Kim
authors: Mi Song
authors: MS
authors: Jung
authors: Sung Hyun
authors: SH
authors: Chung
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D050882:CREB-Binding Protein / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D036145:Ginsenosides / Q000494:pharmacology*; D005943:Gluconeogenesis / Q000235:genetics; D005947:Glucose / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D056945:Hep G2 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D036145:Ginsenosides; D007004:Hypoglycemic Agents; D011720:Pyrazoles; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear; C099713:nuclear receptor subfamily 0, group B, member 2; C516138:dorsomorphin; C026474:ginsenoside Rg2; D050882:CREB-Binding Protein; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D038362:Glycogen Synthase Kinase 3; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose