Life sciences · 2026
Artemether (an artemisinin derivative) suppresses hepatic gluconeogenesis in diabetic mice by activating miR-155-C/EBPβ axis.
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Jia Junshuang, Shen Lingjun, Lin Xia, Han Liuxin, Huang Shihao, Bai Binyi, Li Yingchun, Hong Gengrui, Zhao Ping, Chen Li, Zhou Ziling, Li Xiaoyan, Lin Taoyan, Jiang Bo, Zhou Zhihao, Zhao Wentao, Dai Guanqi, Zhou Ying, Cong Jinge, He Danhua, Peng Zhitao, Shen Hongfen, Wang Jiahong, Xu Kang, Du Tao, Xiao Dong, Lin Xiaolin
Аннотация
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.
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.