PPP1R3C mediates metformin-inhibited hepatic gluconeogenesis
Abstract
BACKGROUND: Metformin has been widely used to alleviate hyperglycemia in patients with type 2 diabetes mainly via suppressing hepatic gluconeogenesis. However, the underlying mechanism remains incompletely clear. Here, we aimed to explore the role of PPP1R3C in metformin-mediated inhibition of hepatic gluconeogenesis.
METHODS: The differentially expressed genes in primary mouse hepatocytes incubated with 8-Br-cAMP and metformin were analyzed by microarrays. Hepatic glucose production and gluconeogenic gene expressions were detected after adenovirus-mediated overexpression or silence of PPP1R3C in vitro and in vivo. The phosphorylation level and location of transducer of regulated CREB activity 2 (TORC2) were determined by Western blot and immunofluorescence.
RESULTS: Metformin and adenovirus-mediated activation of AMPK suppressed 8-Br-cAMP-stimulated Ppp1r3c mRNA expression in primary mouse hepatocytes. Overexpression of PPP1R3C in primary mouse hepatocytes or the livers of wild-type mice promoted hepatic glucose production and gluconeogenic gene expressions. On the contrary, adenovirus-mediated knockdown of PPP1R3C in primary mouse hepatocytes decreased hepatic gluconeogenesis, with the suppression of cAMP-stimulated gluconeogenic gene expressions and TORC2 dephosphorylation. Notably, Ppp1r3c expression was increased in the liver of db/db mice. After PPP1R3C silence in the livers of wild-type and db/db mice, blood glucose levels and hepatic glucose production were markedly…
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