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
  • 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, [email protected].
  • 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, [email protected].
  • 7. the General Hospital of Ningxia Medical University, Yinchuan 750004, China.
PMID: 31113861 DOI: 10.1074/jbc.RA118.007231
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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