1. Academic Validation
  2. The natural product antroalbol H promotes phosphorylation of liver kinase B1 (LKB1) at threonine 189 and thereby enhances cellular glucose uptake

The natural product antroalbol H promotes phosphorylation of liver kinase B1 (LKB1) at threonine 189 and thereby enhances cellular glucose uptake

  • J Biol Chem. 2019 Jul 5;294(27):10415-10427. doi: 10.1074/jbc.RA118.007231.
Fang Wang 1 2 Xiaoyan Yang 1 3 Yanting Lu 1 2 Zhenghui Li 4 Yuhui Xu 1 Jing Hu 1 Jikai Liu 5 Wenyong Xiong 6 7
Affiliations

Affiliations

  • 1 From the State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China.
  • 2 the University of the Chinese Academy of Sciences, Beijing 100049, China, and.
  • 3 the Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650201, China.
  • 4 the School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan 430074, China.
  • 5 the School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan 430074, China, liujikai@mail.scuec.edu.cn.
  • 6 From the State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China, xiong.wenyong@mail.kib.ac.cn.
  • 7 the General Hospital of Ningxia Medical University, Yinchuan 750004, China.
Abstract

Hypoglycemic drugs such as metformin increase glucose uptake and utilization by peripheral tissues to maintain glucose homeostasis, and the AMP-activated protein kinase (AMPK) signaling pathway is an important component of this pharmacological activity. Liver kinase B1 (LKB1) acts as a kinase upstream of AMPK and plays an important regulatory role in glucose metabolism. In recent years, as a tumor suppressor, LKB1's antitumor activity has been widely studied, yet its hypoglycemic activity is not clear. Here, using biochemical and cell viability assays, site-directed mutagenesis, immunoblotting, and immunofluorescence staining, we found that a natural product, antroalbol H isolated from the basidiomycete mushroom Antrodiella albocinnamomea, increases cellular glucose uptake in murine L6 myotubes and 3T3-L1 adipocytes. Of note, our results indicated that this effect is related to LKB1-mediated Thr-172 phosphorylation of AMPKα. Furthermore, we observed that antroalbol H induces the phosphorylation of LKB1 specifically at Thr-189 and changes subcellular localization of LKB1. Finally, antroalbol H treatment strikingly promoted glucose transporter type 4 (GLUT4) translocation to the plasma membrane. We conclude that antroalbol H promotes Thr-189 phosphorylation of LKB1, leading to AMPK activation, revealing this residue as a potential target for increasing glucose uptake, and that antroalbol H therefore has potential for managing hyperglycemia.

Keywords

AMP-activated kinase (AMPK); Basidiomycete; diabetes; energy sensing; fungi; glucose homeostasis; glucose metabolism; glucose transporter type 4 (GLUT4); liver kinase B1 (LKB1); sesquiterpene.

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