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Epigallocatechin Gallate Inhibits Hepatic Glucose Production in Primary Hepatocytes via Downregulating PKA Signaling Pathways and Transcriptional Factor FoxO1
journal contribution
posted on 2019-03-15, 00:00 authored by Xiaopeng Li, Yunmei Chen, James Zheng Shen, Quan Pan, Wanbao Yang, Hui Yan, Huimin Liu, Weiqi Ai, Wang Liao, Shaodong GuoForkhead/winged helix transcription
factor O-class member 1 (FoxO1)
is a key mediator of insulin and glucagon signaling in control of
glucose homeostasis. Although epigallocatechin gallate (EGCG) has
attracted interest owing to its potential to combat hyperglycemic
diabetes, molecular mechanisms underlying its antihyperglycemic effect,
in particular the effect on FoxO1, is poorly understand. This study
aims to assess the impact of EGCG on the glucagon signaling pathway
in regulating glucose metabolism. Primary hepatocytes from wild-type
(WT), liver-specific FoxO1 knock out (FKO), and FoxO1-S273D knock-in
(KI) mice were isolated, cultured, and treated with EGCG and/or glucagon.
Our data showed the treatment of 10 μM EGCG for 6 h decreased
hepatic glucose production by 20 and 23% in WT and FKO primary hepatocytes,
respectively. EGCG repressed both gluconeogenesis and glycogenolysis
in primary hepatocytes, coupled with activating AMPK. In addition,
EGCG decreased mitochondrial oxygen consumption. We further investigated
the effects of EGCG on glucagon-stimulated cAMP/PKA signaling pathway.
EGCG reduced p-PKA-T197/T-PKA and p-CREB-S133/T-CREB levels by 39
and 20%, blocked p-FoxO1-S273, and suppressed nuclear FoxO1 translocation,
suggesting that FoxO1 and CREB were possible downstream targets. A
novel mechanism of EGCG in restraining hepatic glucose production
(HGP) is through antagonizing glucagon signaling and suppressing FoxO1
via Ser273. EGCG may serve as a promising compound for regulating
glucose homeostasis.