TY - JOUR
T1 - SIRT1 activation by methylene blue, a repurposed drug, leads to AMPK-mediated inhibition of steatosis and steatohepatitis
AU - Shin, Seo Young
AU - Kim, Tae Hyun
AU - Wu, Hongmin
AU - Choi, Young Hee
AU - Kim, Sang Geon
PY - 2014/3/15
Y1 - 2014/3/15
N2 - Sirtuins maintain energy balance. Particularly, sirtuin 1 (SIRT1) activation mimics calorie restriction and nutrient utilization. However, no medications are available for the up-regulation of SIRT1. Methylene blue (MB) had been in clinical trials for the treatment of neurological diseases. This study investigated the effect of MB on sirtuin expression in association with the treatment of steatosis and steatohepatitis, and explored the underlying basis. The effects of MB on mitochondrial function, molecular markers, pharmacokinetics, and histopathology were assessed using hepatocyte and/or mouse models. Immunoblotting, PCR and reporter assays were done for molecular experiments. After oral administration, MB was well distributed in the liver. MB treatment increased NAD+/NADH ratio in hepatocytes. Of the major forms, MB treatment up-regulated SIRT1, and thereby decreased PGC-1α acetylation. Consistently, hepatic mitochondrial DNA contents and oxygen consumption rates were enhanced. MB treatment also notably activated AMPK, CPT-1 and PPARα: the AMPK activation relied on SIRT1. Activation of LXRα and the induction of SREBP-1c and its target genes by T0901317 were diminished by MB. In addition, MB treatment antagonized the ability of palmitate to acetylate PGC-1α, and increase SERBP-1c, FAS, and ACC levels. In mice fed on a high-fat diet for 8 weeks, MB treatment inhibited excessive hepatic fat accumulation and steatohepatitis. The ability of MB to activate SIRT1 promotes mitochondrial biogenesis and oxygen consumption and activates AMPK, contributing to anti-lipogenesis in the liver. Our results provide new information on the potential use of MB for the treatment of steatosis and steatohepatitis.
AB - Sirtuins maintain energy balance. Particularly, sirtuin 1 (SIRT1) activation mimics calorie restriction and nutrient utilization. However, no medications are available for the up-regulation of SIRT1. Methylene blue (MB) had been in clinical trials for the treatment of neurological diseases. This study investigated the effect of MB on sirtuin expression in association with the treatment of steatosis and steatohepatitis, and explored the underlying basis. The effects of MB on mitochondrial function, molecular markers, pharmacokinetics, and histopathology were assessed using hepatocyte and/or mouse models. Immunoblotting, PCR and reporter assays were done for molecular experiments. After oral administration, MB was well distributed in the liver. MB treatment increased NAD+/NADH ratio in hepatocytes. Of the major forms, MB treatment up-regulated SIRT1, and thereby decreased PGC-1α acetylation. Consistently, hepatic mitochondrial DNA contents and oxygen consumption rates were enhanced. MB treatment also notably activated AMPK, CPT-1 and PPARα: the AMPK activation relied on SIRT1. Activation of LXRα and the induction of SREBP-1c and its target genes by T0901317 were diminished by MB. In addition, MB treatment antagonized the ability of palmitate to acetylate PGC-1α, and increase SERBP-1c, FAS, and ACC levels. In mice fed on a high-fat diet for 8 weeks, MB treatment inhibited excessive hepatic fat accumulation and steatohepatitis. The ability of MB to activate SIRT1 promotes mitochondrial biogenesis and oxygen consumption and activates AMPK, contributing to anti-lipogenesis in the liver. Our results provide new information on the potential use of MB for the treatment of steatosis and steatohepatitis.
KW - Lipogenesis
KW - Methylene blue
KW - Mitochondria
KW - SIRT1
KW - Steatoheptitis
UR - http://www.scopus.com/inward/record.url?scp=84893697774&partnerID=8YFLogxK
U2 - 10.1016/j.ejphar.2014.01.035
DO - 10.1016/j.ejphar.2014.01.035
M3 - Article
C2 - 24486702
AN - SCOPUS:84893697774
SN - 0014-2999
VL - 727
SP - 115
EP - 124
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 1
ER -