Artemether (an artemisinin derivative) suppresses hepatic gluconeogenesis in diabetic mice by activating miR-155-C/EBPβ axis.

AIMS: Hepatic gluconeogenesis suppression represents a strategy to combat diabetes-induced hyperglycemia. Although artemisinin (ART) and its derivatives (e.g., artemether (ATM)) exhibit anti-diabetic properties, their roles in regulating hepatic gluconeogenesis and underlying mechanisms remain incompletely understood. Moreover, the involvement of miR-155 in this process has not been explored.

MATERIALS AND

METHODS

We employed RNA-sequencing (RNA-seq), TMT-based proteomics, targeted metabolomics and qRT-PCR to evaluate molecular changes in glucose metabolism-related pathways. Gain- and loss-of-function approaches in mice were used to assess the physiological impacts of miR-155 on glucose homeostasis.

KEY FINDINGS: Hepatic miR-155 expression was downregulated in fasted and diabetic mice. Global or hepatocyte-specific transgenic overexpression of miR-155 in mice suppressed hepatic gluconeogenesis and led to hypoglycemia, whereas miR-155 deficiency enhanced glucose production and hyperglycemia. Additionally, miR-155 negatively modulated hepatic gluconeogenic gene expression in a hepatocyte-autonomous manner. Hepatocyte-specific miR-155 overexpression in mice enhanced glycogen storage, increased phosphorylation of AKT and GSK-3β, and elevated the expression of Gys2 and Gck, accompanied by improved glucose tolerance and insulin sensitivity. Multi-omics (RNA-seq, proteomics, and metabolomics) profiling of livers from Rm155LG/Alb-Cre mice revealed that miR-155 overexpression reprogrammed hepatic glucose metabolism toward enhanced glycogenesis, suppressed gluconeogenesis, and activated pentose phosphate pathway. Mechanistically, miR-155 inhibited gluconeogenesis by directly targeting C/EBPβ in mice. This study is the first to reveal that ATM ameliorated hyperglycemia in diabetic mice by inhibiting hepatic gluconeogenesis, at least partially via activating miR-155-C/EBPβ axis.

SIGNIFICANCE: Our study identifies miR-155 and ATM as novel regulators of hepatic gluconeogenesis, highlighting their potential as therapeutic targets for diabetes-associated hyperglycemia.