Mechanism And Functional Study For Regulation Of AMPK Activity By UHRF1

UHRF1 is an important regulatory factor for DNA methylation,and its function in DNA maintenance methylation has been well studied.In addition,other studies have shown that UHRF1 is involved in DNA damage repair,but whether there are other new biological functions of UHRF1 is unclear.AMPK is an important cell energy sensor.When the cell is in the state of energy shortage,AMPK will be activated.After activation,AMPK can phosphorylate different downstream substrates to promote catabolism and inhibit anabolism,and finally make the cell reach the state of energy balance.Our study found that UHRF1 can interact with AMPK.UHRF1 can significantly inhibit AMPK kinase activity in different cell lines and this regulation is independent of its E3 ubiquitin ligase activity.We also found that UHRF1 can regulate glycolysis and lipid metabolism through AMPK.Further experiments showed that UHRF1 can negatively control the activity of AMPK through recruiting phosphatase PP2 A to dephosphorylate AMPK in the nucleus.Since AMPK can shuttling between cytoplasm and nucleus,so UHRF1 can suppress AMPK activities both in nucleus and cytoplasm.Finally,we specifically overexpressed UHRF1 in the liver of mice by injecting adenovirus into the tail vein and found that the overall metabolic indexes of mice,including blood glucose,blood lipid and liver lipid levels,were significantly changed after overexpression of UHRF1.Meanwhile,the activity of AMPK in the liver was also significantly inhibited.We obtained similar results by constructing the transgenic mouse model of conditional overexpression of UHRF1 in the liver.These results indicated that UHRF1 could negatively regulate the activity of AMPK in vivo.In conclusion,our study found that UHRF1 can regulate cell metabolism through controlling AMPK kinase activity.