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Orphan Nuclear Receptors and Metabolic Disease Hueng-Sik Choi Hormone Research Center, Chonnam National University, Gwangju, 500-757 Korea Small heterodimer partner (SHP; NR0B2) is a member of the nuclear receptor superfamily that lacks a conventional DNA binding domain. It has been demonstrated that the SHP acts as a repressor of transcriptional activities of a number of nuclear receptors, including GR, ER, AR, TR, RAR, RXR, CAR, PXR, HNF4 , LRH-1, ERR , , Nur77 , PPARgama and LXR. Variety of receptors sensitive to inhibition by SHP suggests a central role for SHP in modulation of nuclear receptor signaling pathways. SHP is expressed in a wide variety of tissues, including heart, brain, liver, spleen, adrenal gland, small intestine, and pancreas. Moreover, human SHP gene is located on chromosome 1p36.1 and consists of two exons separated by an intron. SHP gene transcription is regulated by several members of the nuclear receptor superfamily including the FXR, LXR, HNF4 , LRH-1, ER and ERR- . Moreover, SHP plays a key role in the regulation of key enzyme genes involved in the glucose, lipid, cholesterol metabolism. Recent progresses on the elucidation of molecular mechanism of SHP gene expression, function and metabolic homeostasis will be discussed.