In this study, we found that nuclear receptors FXR and LXR (originally characterized as regulatory factors involved in cholesterol/bile acid homeostasis) regulate the expression of Oct3/4, a marker for cell differentiation, in both normal renal-derived cell line HK-2 and renal adenocarcinoma cell line ACHN. Down-regulation of Oct3/4 expression by activating FXR and LXR occurs only in normal renal cell-derived HK-2 cells. We also found that the RNA-binding protein, ELAVL2, oppositely regulates Oct3/4 expressions in HK-2 and ACHN cells. Moreover, we revealed that LXR-alpha and LXR-beta regulate each other's expression. Although an LXR-beta-specific agonist is assumed to be the basis for an anti-arteriosclerotic drug that only stimulates reverse cholesterol transport, our findings show that the development of such an anti-arteriosclerotic drug would require further elucidation of the complex mechanism of LXR-alpha and LXR-beta regulation.

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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.