Epigallocatechin Gallate Inhibits Hepatic Glucose Production in Primary Hepatocytes via Downregulating PKA Signaling Pathways and Transcriptional Factor FoxO1

Forkhead/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.