SHP is an orphan nuclear receptor containing the dimerization and ligand-binding domains found in other nuclear receptors, but lacking the conserved DNA binding domain. SHP is specifically expressed in liver and other tissues, including fetal liver and adrenal gland, as well as adult spleen and small intestine. In addition, SHP is highy expressed in the murine macrophage cell line RAW 264.7 but suppressed by oxLDL and 13-HODE, which is a ligand for PPARg. SHP interacts with nuclear receptors, including thyroid receptor, retinoic acid receptors (RAR and RXR) and estrogen receptors (ERa and ERb). SHP functions as a negative regulator of these receptors by at least three mechanisms: inhibition of DNA binding via dimerization, direct antagonism of coactivator function through competition and possibly transrepression via recruitment of putative corepressors. In oxLDL-treated, resting macrophage cells, SHP acts as a transcription coactivator of NFkB, suggesting that SHP is a modulatory component in the regulation of the transcriptional activities of NFkB. Lastly, negative feedback regulation of a hepatic bile acid transporter, NTCP, is controlled by bile acid-activated FXR via induction of SHP to protect the hepatocyte from bile acid-mediated damage in cholestatic conditions.