OPEN IN READ APP
JOURNAL ARTICLE

SIRT1 activation by methylene blue, a repurposed drug, leads to AMPK-mediated inhibition of steatosis and steatohepatitis

Seo Young Shin, Tae Hyun Kim, Hongmin Wu, Young Hee Choi, Sang Geon Kim
European Journal of Pharmacology 2014 March 15, 727: 115-24
24486702
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.

Full Text Links

Find Full Text Links for this Article

Discussion

You are not logged in. Sign Up or Log In to join the discussion.

Related Papers

Available on the App Store

Available on the Play Store
Remove bar
Read by QxMD icon Read
24486702
×

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"