Role of nuclear receptor SHP in metabolism and cancer

Abstract

Small heterodimer partner (SHP, NR0B2) is a unique member of the nuclear receptor (NR) superfamily that contains the dimerization and ligand-binding domain found in other family members, but lacks the conserved DNA-binding domain. The ability of SHP to bind directly to multiple NRs is crucial for its physiological function as a transcriptional inhibitor of gene expression. A wide variety of interacting partners for SHP have been identified, indicating the potential for SHP to regulate an array of genes in different biological pathways. In this review, we summarize studies concerning the structure and target genes of SHP and discuss recent progress in understanding the function of SHP in bile acid, cholesterol, triglyceride, glucose, and drug metabolism. In addition, we review the regulatory role of SHP in microRNA (miRNA) regulation, liver fibrosis and cancer progression. The fact that SHP controls a complex set of genes in multiple metabolic pathways suggests the intriguing possibility of developing new therapeutics for metabolic diseases, including fatty liver, dyslipidemia and obesity, by regulating SHP with small molecules. To achieve this goal, more progress regarding SHP ligands and protein structure will be required. Besides its metabolic regulatory function, studies by us and other groups provide strong evidence that SHP plays a critical role in the development of cancer, particularly liver and breast cancer. An increased understanding of the fundamental mechanisms by which SHP regulates the development of cancers will be critical in applying knowledge of SHP in diagnostic, therapeutic or preventive strategies for specific cancers. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease.

Figure 1. Domain structure of the orphan nuclear receptor SHP

Classical nuclear receptor (NR) contains five major functional domains: the N-terminal ligand-independent transactivation domain (A/B domain), the DNA binding domain (DBD or C domain), hinge region (D domain), the C-terminal ligand-binding domain (LBD or E domain), and the ligand-dependent transactivation domain (AF2 or F domain). Compared to the classical NRs, SHP contains the dimerization and LBD domain, but lacks the conserved DBD. SHP represses the transcriptional activities of its targets gene by utilizing two functional LXXLL-related motifs (also called NR-boxes) which are located in the putative N-terminal helix 1 of the LBD and in the C-terminal region of helix 5.

Figure 2. Schematic overview of nuclear receptors (NRs) and transcription receptors (TFs) regulating the promoter of the human SHP gene

Location of the binding sites of NRs and TFs and the consensus sequences are indicated in the human SHP gene promoter. NRs that target SHP promoter include hepatocyte nuclear factor 4a (HNF4α), steroidogenic factor-1 (SF-1), liver receptor homolog-1 (LRH-1), farnesoid X receptor (FXR), estrogen receptor a (ERα), liver X receptor α (LXRα), upstream stimulatory factor-1 (USF-1), estrogen receptor related receptor γ (ERRγ), and peroxisome proliferator-activated receptor γ (PPARγ). TFs that induce SHP expression include E47, c-Jun, sterol regulatory element binding protein -1c (SREBP-1c) and circadian locomotor output cycles kaput (CLOCK)/brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1(Bmal1).

Figure 3. Model of three distinct transcriptional repression mechanisms for SHP

SHP represses nuclear receptor (NR) or transcription factor (TF) mediated transactivation by competition for coactivator binding to NR (I), recruitment of SHP-associated corepressors (II), and inhibition of DNA binding (III). SHP can utilize these three inhibitory steps alternatively or sequentially in a cell type and target gene specific manner.

Figure 4. Integrated view of SHP as a central transcriptional coregulator in diverse physiological pathways in the liver

Activation pathways are shown as broken blue arrows and inhibitory pathways are shown as broken red lines. FA, fatty acid; TG, triglyceride; VLDL, very low density lipoprotein; CYP7A1, cytochrome P450 enzyme cholesterol 7α-hydroxylase; G6P, glucose-6-phosphatase; HNF-4α, hepatocyte nuclear factor 4 α; JNK, c-jun N-terminal kinase; LRH-1, liver receptor homolog-1; LXR, liver X receptor; MTP, microsomal triglyceride transfer protein; PEPCK, phosphoenolpyruvate carboxykinase; PPARγ, peroxisome proliferator activated receptor γ; SHP, small heterodimer partner; SREBP-1c, sterol regulatory element binding protein-1c; WAT, white adipose tissue; and BAT, brown adipose tissue.