Nuclear receptors (NRs) comprise one of the most abundant classes of transcriptional regulators of metabolic diseases and have emerged as promising pharmaceutical targets. Small heterodimer partner (SHP; NR0B2) is a unique orphan NR lacking a DNA-binding domain but contains a putative ligand-binding domain. SHP is a transcriptional regulator affecting multiple key biological functions and metabolic processes including cholesterol, bile acid, and fatty acid metabolism, as well as reproductive biology and glucose-energy homeostasis. About half of all mammalian NRs and several transcriptional coregulators can interact with SHP. The SHP-mediated repression of target transcription factors includes at least three mechanisms including direct interference with the C-terminal activation function 2 (AF2) coactivator domains of NRs, recruitment of corepressors, or direct interaction with the surface of NR/transcription factors. Future research must focus on synthetic ligands acting on SHP as a potential therapeutic target in a series of metabolic abnormalities. Current understanding about the pleiotropic role of SHP is examined in this paper, and principal metabolic aspects connected with SHP function will be also discussed. 1. Introduction Nuclear receptors (NRs) constitute a unique family of ligand-modulated transcription factors. NRs mediate cellular response to small lipophilic endogenous and exogenous ligands [1, 2] and are responsible for sensing a number of hormones, including steroid and thyroid hormones, and act as positive and negative regulators of the expression of specific genes [3–5]. Therefore, NRs play a central role in many aspects of mammalian development, as well as lipid homeostasis, physiology, and metabolism. NRs make up one of the most abundant classes of transcriptional regulators in the body and have emerged as promising pharmaceutical targets. Classically, NRs consist of several functional domains, that is, a variable N-terminal ligand-independent transactivation domain (which often exhibits a constitutive transcription activation function (AF-1)), a highly conserved DNA-binding domain (DBD) that contains two zinc fingers, a hinge domain (a variable linker region), and a multifunctional C-terminal domain. Furthermore, the C-terminal domain includes the ligand binding (LBD), the dimerization interface, and the ligand-dependent transactivation domain AF-2 [1, 6]. Small heterodimer partner (SHP; NR0B2 for nuclear receptor subfamily 0, group B, member 2; MIM number 604630, 601665) is a member of the mammalian NR superfamily, due to the
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