Ouabagenin, an aglycone of cardiotonic steroid ouabain, functions as LXR ligand but avoids the increase in the SREBP-1 by inducing Krüppel-like factor 15

Abstract

Liver X receptor (LXR)-alpha and LXR-beta are nuclear receptors activated by oxysterols. They exhibit differential expression patterns and may perform different functional roles. Here we show that LXR-alpha and LXR-beta mutually regulate the expression levels of their counter parts in the normal hepatocyte-derived cell line Fa2N-4. In addition, we demonstrate that ouabagenin (OBG), which was identified as a naturally occurring LXR ligand without causing hepatic steatosis, dramatically increases the expression of LXR-alpha in Fa2N-4 cells that overexpress LXR-beta. However, the expression level of sterol response element binding protein 1c (SREBP-1c), a known target of LXR-alpha, remains marginal in OBG-treated Fa2N-4 cells, in which LXR-alpha expression is upregulated by LXR-beta. Furthermore, we show that OBG stimulates the expression of Krüppel-like factor 15 (KLF15) that is known to form a repressive complex with LXR/RXR and corepressor RIP140, thereby reducing SREBP-1c expression. Thus, we propose a novel mechanism that OBG avoids the increase in the expression of SREBP-1c through the upregulation of KLF15.