Activation of AMP-activated protein kinase (AMPK) through inhibiting interaction with prohibitins

Shuhei Kanagaki; Yusuke Tsutsui; Naoki Kobayashi; Takashi Komine; Minoru Ito; Yunike Akasaka; Michiaki Nagasawa; Tomohiro Ide; Naoki Omae; Kazuhisa Nakao; Makoto Rembutsu; Maki Iwago; Aki Yonezawa; Yusei Hosokawa; Tetsuya Hosooka; Wataru Ogawa; Koji Murakami

doi:10.1016/j.isci.2023.106293

Activation of AMP-activated protein kinase (AMPK) through inhibiting interaction with prohibitins

iScience. 2023 Feb 28;26(4):106293. doi: 10.1016/j.isci.2023.106293. eCollection 2023 Apr 21.

Authors

Shuhei Kanagaki¹, Yusuke Tsutsui¹, Naoki Kobayashi¹, Takashi Komine¹, Minoru Ito¹, Yunike Akasaka¹, Michiaki Nagasawa¹, Tomohiro Ide¹, Naoki Omae¹, Kazuhisa Nakao¹, Makoto Rembutsu¹, Maki Iwago¹, Aki Yonezawa¹, Yusei Hosokawa², Tetsuya Hosooka², Wataru Ogawa², Koji Murakami¹

Affiliations

¹ Watarase Research Center, Kyorin Pharmaceutical Co. Ltd., Shimotsuga-gun, Tochigi 329-0114, Japan.
² Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.

Abstract

5'-Adenosine monophosphate-activated protein kinase (AMPK) is a potential therapeutic target for various medical conditions. We here identify a small-molecule compound (RX-375) that activates AMPK and inhibits fatty acid synthesis in cultured human hepatocytes. RX-375 does not bind to AMPK but interacts with prohibitins (PHB1 and PHB2), which were found to form a complex with AMPK. RX-375 induced dissociation of this complex, and PHBs knockdown resulted in AMPK activation, in the cultured cells. Administration of RX-375 to obese mice activated AMPK and ameliorated steatosis in the liver. High-throughput screening based on disruption of the AMPK-PHB interaction identified a second small-molecule compound that activates AMPK, confirming the importance of this interaction in the regulation of AMPK. Our results thus indicate that PHBs are previously unrecognized negative regulators of AMPK, and that compounds that prevent the AMPK-PHB interaction constitute a class of AMPK activator.

Keywords: Biochemistry; Endocrinology; Small molecule.