Epigallocatechin-3-gallate (EGCG), a green tea polyphenol, suppresses hepatic gluconeogenesis through 5'-AMP-activated protein kinase.
Epigallocatechin-3-gallate (EGCG), a main catechin of green tea, has been suggested to inhibit hepatic gluconeogenesis. However, the exact role and related mechanism have not been established. In this study, we examined the role of EGCG in hepatic gluconeogenesis at concentrations that are reachable by ingestion of pure EGCG or green tea, and are not toxic to hepatocytes. Our results show in isolated hepatocytes that EGCG at relatively low concentrations (<or=1 microm) inhibited glucose production via gluconeogenesis and expression of key gluconeogenic genes. EGCG was not toxic at these concentrations while demonstrating significant cytotoxicity at 10 mum and higher concentrations. EGCG at 1 mum or lower concentrations effective in suppressing hepatic gluconeogenesis did not activate the insulin signaling pathway, but activated 5'-AMP-activated protein kinase (AMPK). The EGCG suppression of hepatic gluconeogenesis was prevented by blockade of AMPK activity. In defining the mechanism by which EGCG activates AMPK, we found that the EGCG activation of AMPK was mediated by the Ca(2+)/calmodulin-dependent protein kinase kinase (CaMKK). Furthermore, our results show that the EGCG activation of AMPK and EGCG suppression of hepatic gluconeogenesis were both dependent on production of reactive oxygen species (ROS), which was a known activator of CaMKK. Together, our results demonstrate an inhibitory role for EGCG in hepatic gluconeogenesis and shed new light on the mechanism by which EGCG suppresses gluconeogenesis.
Collins
Qu Fan
QF
Translational Biology, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Liu
Hui-Yu
HY
Pi
Jingbo
J
Liu
Zhenqi
Z
Quon
Michael J
MJ
Cao
Wenhong
W
D055372:AMP-Activated Protein Kinases; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D005943:Gluconeogenesis / Q000187:drug effects*; D022781:Hepatocytes / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000737:chemistry; D007328:Insulin / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009097:Multienzyme Complexes / Q000378:metabolism / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology*; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species; D015398:Signal Transduction; D013662:Tea
D000975:Antioxidants; D007328:Insulin; D009097:Multienzyme Complexes; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D013662:Tea; D002392:Catechin; D006861:Hydrogen Peroxide; C045651:epigallocatechin gallate; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases