TY - JOUR
T1 - Ouabagenin is a naturally occurring LXR ligand without causing hepatic steatosis as a side effect
AU - Tamura, Satoru
AU - Okada, Maiko
AU - Kato, Shigeaki
AU - Shinoda, Yasuharu
AU - Shioda, Norifumi
AU - Fukunaga, Kohji
AU - Ui-Tei, Kumiko
AU - Ueda, Minoru
N1 - Funding Information:
The authors thank Dr. Haruka Oishi and Mr. Tetsuro Abe for their technical assistance. This work was also supported in part by a Grant-in-Aid for Scientific Research (no. 23102012) on Innovative Areas “Chemical Biology of Natural Products” to MU and MO from MEXT, Japan; a Grant-in-Aid for Scientific Research (no. 26282207 and no. 17H00885 to MU; no. no. 24102511 and no. 24102511 to MO); JSPS A3 Foresight Program to MU; and JSPS KAKENHI (no. JP15K01817 to ST).
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41598-018-20663-z
DO - 10.1038/s41598-018-20663-z
M3 - Article
C2 - 29396543
AN - SCOPUS:85041558478
SN - 2045-2322
VL - 8
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 2305
ER -