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Herbal medicine of Kursi Wufarikun Ziyabit inhibits mitochondrial ATP production to activate AMPK in hepatocytes in therapy of type 2 diabetes

By Mireguli Yasen, Lan Jiang, Mizhgona Sharofova, Xuelei Xin, Yusuf Nuraliev, Jianping Ye, Haji Akber Aisa

Posted 29 Sep 2020
bioRxiv DOI: 10.1101/2020.09.28.316349

The herbal medicine of Kursi Wufarikun Ziyabit contains two herbs ( Geranium collinum Steph.ex Willd and Hypericum Scabrum Lnn) in the formula of ethnomedicine. It is usually used in the treatment of diabetes mellitus with a significant therapeutic efficacy. However, the molecular mechanism remains unknown for the action of medicine. In this study, we investigated the mechanism with a focus on an extract (GC30) of the medicine in the regulation of energy metabolism in hepatocytes. GC30 was prepared from a crude extract of the medicine through elution of an AB-8 macro porous resin column loaded with the medicine in 30% ethanol. GC30 exhibited an activity in the inhibition of triglyceride (TG) accumulation in the mouse hepatocytes through a suppression of SREBP1c activity. FGF21 (fibroblast growth factor 21) expression was induced by GC30 in a dosage-dependent manner at concentrations of 25 - 100 μg/ml. The induction was observed in mRNA and protein of FGF21, which were peaked at 2 hours and lasted for 8 hours in the response to GC30 (100 μg/ml). The transcription of FGF21 gene was induced by GC30 for an increase in the FGF21 gene promoter activity. AMPK and PKA activities were induced by GC30 with an elevation in their phosphorylation status, which were associated with a reduction in ATP abundance and an increase in CREB phosphorylation in cells treated with GC30. Oxygen consumption of mitochondria was inhibited in the hepatocytes by GC30. These activities of GC30 were similar to those of diabetes medicines including metformin and berberine. The data suggest that GC30 inhibited ATP production in mitochondria to activate AMPK and PKA in the hepatocytes to induce FGF21 expression. This study suggests a novel activity of the herbal medicine in the regulation of glucose and lipid metabolism in the hepatocytes. ### Competing Interest Statement The authors have declared no competing interest.

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