Ouabagenin is a naturally occurring LXR ligand without causing hepatic steatosis as a side effect

  • Sci Rep. 2018 Feb 2;8(1):2305. doi: 10.1038/s41598-018-20663-z.
Satoru Tamura  1  2 ,  Maiko Okada  3  4 ,  Shigeaki Kato  5  6 ,  Yasuharu Shinoda  7 ,  Norifumi Shioda  7 ,  Kohji Fukunaga  7 ,  Kumiko Ui-Tei  8 ,  Minoru Ueda  9
Affiliations
  • 1. Department of Chemistry, Graduate School of Science, Tohoku University, Sendai, Miyagi, 980-8578, Japan.
  • 2. School of Pharmacy, Iwate Medical University, Shiwa-gun, Iwate, 028-3694, Japan.
  • 3. Institute of Medical Science, St. Marianna University Graduate School of Medicine, Kawasaki, Kanagawa, 970-8551, Japan.
  • 4. Genome regulation and Molecular Pharmacogenomics, School of Bioscience and Biotechnology, Tokyo University of Technology, Hachioji, Tokyo, 192-0982, Japan.
  • 5. Iwaki Meisei University, Iwaki, Fukushima, 970-8551, Japan.
  • 6. Research Institute of Innovative Medicine, Tokiwa Foundation, Iwaki, Fukushima, 972-8322, Japan.
  • 7. Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, 980-8578, Japan.
  • 8. Graduate School of Science, The University of Tokyo, Tokyo, 113-0032, Japan.
  • 9. Department of Chemistry, Graduate School of Science, Tohoku University, Sendai, Miyagi, 980-8578, Japan. [email protected].
PMID: 29396543 DOI: 10.1038/s41598-018-20663-z
Abstract

Ouabagenin (OBG) is an aglycone of the cardiotonic steroid ouabain and until now was considered a biologically inactive biosynthetic precursor. Herein, we revealed that OBG functions as a novel class of ligand for the liver X receptor (LXR). Luciferase reporter assays and in silico docking studies suggested that OBG has LXR-selective agonistic activity. In addition, OBG repressed the expression of epithelial Sodium Channel (ENaC), a LXR target gene, without causing hepatic steatosis, a typical side effect of conventional LXR ligands. This remarkable biological activity can be attributed to a unique mode of action; the LXR Agonist activity mainly proceeds through the LXRβ subtype without affecting LXRα, unlike conventional LXR ligands. Thus, OBG is a novel class of LXR ligand that does not cause severe side effects, with potential for use as an antihypertensive diuretic or a tool compound for exploring LXR subtype-specific biological functions.

Products