Berberine activates AMPK to suppress proteolytic processing, nuclear translocation and target DNA binding of SREBP-1c in 3T3-L1 adipocytes

초록

AMP-activated protein kinase (AMPK) and sterol regulatory element binding protein (SREBP) -1c are major therapeutic targets in the treatment of metabolic diseases. In the present study, the fat-reducing mechanisms of berberine (BBR), a natural isoquinoline, was investigated by examining the AMPK-mediated modulation of SREBP-1c in 3T3-L1 adipocytes. BBR activated AMPK in a dose-and timedepen-dent manner, and increased the phosphorylation of the 125-kDa precursor form of SREBP-1c, which suppressed its proteolytic processing into the mature 68-kDa form and its subsequent nuclear translocation. The binding of nuclear SREBP-1c to its E-box motif-containing target DNA sequence was decreased following treatment with BBR, which led to a decrease in the expression of lipogenic genes and subsequently reduced intracellular fat accumulation. Transfection with AMPK alpha 1 siRNA, and not control siRNA, inhibited BBR-induced phosphorylation of the 125-kDa SREBP-1c, which confirmed that AMPK was responsible for phosphorylating SREBP-1c. AMPK alpha 1 siRNA transfection rescued the proteolytic processing, nuclear translocation and target DNA binding of SREBP-1c that had been suppressed by BBR. In addition, BBR-induced suppression of lipogenic gene expression and intracellular fat accumulation were rescued by AMPK alpha 1 siRNA transfection. In conclusion, the results of the present study demonstrate that BBR activates AMPK to induce phosphorylation of SREBP-1c, thereby suppressing proteolytic processing, nuclear translocation and target DNA binding of SREBP-1c, which leads to a reduction in lipogenic gene expression and intracellular fat accumulation. The results of the present study indicate that BBR may be a potential candidate for the development of drugs to treat obesity.

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