https://www.cell.com/molecular-cell/pdf/S1097-2765(00)00051-4.pdf

A Regulatory Cascade of the Nuclear Receptors FXR, SHP-1, and LRH-1 Represses Bile Acid Biosynthesis

I. Introduction II. Nuclear Receptors: General Concepts A. Anatomy of nuclear receptors B. Mechanisms of action III. Orphan Nuclear Receptors A. Definition B. Nomenclature C. Structural and functional diversity IV. Novel Hormone Response Systems: RXR and Its Heterodimeric Partners A. RXR: rexinoids B. PPAR: multiple ligands, multiple functions C. PXR: pregnanes, xenobiotic compounds, and benzoate derivatives D. CAR (constitutive androstane receptor): androstanes and phenobarbital E. LXR: control of cholesterol metabolism by oxysterols F. FXR: bile acids receptor V. Orphans in Search of a Home A. HNF4: diabetes and possible regulation by acyl-coenzyme A (CoA) thioesters B. FTZ-F1: steroidogenesis and sexual development C. Rev-Erb: singular members of the superfamily D. ROR: neuron development and T cell selection E. TR2: the testis receptors F. TLX: forebrain development G. COUP-TF: neurogenesis, angiogenesis, and heart development H. ERR: placenta development and control of lipid metabolism I. NGFI-B: hyp...

/pdf/orphan-nuclear-receptors-from-gene-to-function-28jgs4505b.pdf

Orphan nuclear receptors: from gene to function.

I. Introduction II. The Initial Identification of SF-1 as a Key Determinant of Steroid Hormone Biosynthesis A. Overview of steroidogenesis B. SF-1 and the regulation of steroidogenesis C. Cloning and structural characterization of SF-1 1. Structural features of SF-1 2. Multiple transcripts are encoded by the gene encoding SF-1 3. The gene encoding SF-1 is evolutionarily conserved in vertebrates and invertebrates III. Characterization of Sites of SF-1 Expression and Identification of Its Target Genes A. Profiles of SF-1 expression 1. Adult steroidogenic tissues 2. Embryonic steroidogenic tissues 3. Other sites of SF-1 expression B. Target genes regulated by SF-1 1. Steroidogenic cells 2. Sertoli cells 3. Gonadotropes 4. VMH IV. The Roles Of SF-1 in Vivo: Targeted Gene Disruption to Create SF-1 Knockout Mice A. General features of the SF-1 knockout mice B. Primary steroidogenic tissues in SF-1 knockout mice C. Pituitary and hypothalamic defects in SF-1 knockout mice V. Perspectives and Future Directions A. ...

/pdf/steroidogenic-factor-1-a-key-determinant-of-endocrine-32ewp9n81e.pdf

Steroidogenic Factor 1: A Key Determinant of Endocrine Development and Function

I. Introduction II. Development A. Embryonic adrenal development B. Fetal adrenal development C. Neonatal adrenal development D. Growth E. Functional development 1. Ontogeny of steroidogenic activity 2. Functional zonation and ontogeny of steroidogenic enzyme expression 3. Responsiveness to ACTH III. Regulation A. The fetal pituitary and ACTH B. Growth factors 1. Basic fibroblast growth factor (bFGF) 2. Epidermal growth factor (EGF) 3. Insulin-like growth factors I and II (IGF-I and IGF-II) 4. Activin/inhibins 5. TGFβ C. Nuclear receptors/transcription factors D. Placental factors 1. Human CG (hCG) 2. Placental CRH and ACTH 3. Indirect effect of placental glucocorticoid metabolism 4. Placental estrogens IV. Physiology A. Placental estrogen formation B. Timing of parturition and fetal maturation V. Summary

/pdf/developmental-and-functional-biology-of-the-primate-fetal-3a8vv49pkn.pdf

Developmental and functional biology of the primate fetal adrenal cortex.

The metabolic nuclear receptors act as metabolic and toxicological sensors, enabling the organism to quickly adapt to environmental changes by inducing the appropriate metabolic genes and pathways. Ligands for these metabolic receptors are compounds from dietary origin, intermediates in metabolic pathways, drugs, or other environmental factors that, unlike classical nuclear receptor ligands, are present in high concentrations. Metabolic receptors are master regulators integrating the homeostatic control of (a) energy and glucose metabolism through peroxisome proliferator-activated receptor gamma (PPARgamma); (b) fatty acid, triglyceride, and lipoprotein metabolism via PPARalpha, beta/delta, and gamma; (c) reverse cholesterol transport and cholesterol absorption through the liver X receptors (LXRs) and liver receptor homolog-1 (LRH-1); (d) bile acid metabolism through the farnesol X receptor (FXR), LXRs, LRH-1; and (e) the defense against xeno- and endobiotics by the pregnane X receptor/steroid and xenobiotic receptor (PXR/SXR). The transcriptional control of these metabolic circuits requires coordination between these metabolic receptors and other transcription factors and coregulators. Altered signaling by this subset of receptors, either through chronic ligand excess or genetic factors, may cause an imbalance in these homeostatic circuits and contribute to the pathogenesis of common metabolic diseases such as obesity, insulin resistance and type 2 diabetes, hyperlipidemia and atherosclerosis, and gallbladder disease. Further studies should exploit the fact that many of these nuclear receptors are designed to respond to small molecules and turn them into therapeutic targets for the treatment of these disorders.

Nuclear receptors and the control of metabolism.

The cytochrome P450 steroid hydroxylases are coordinately regulated by steroidogenic factor 1 (SF-1), a protein expressed selectively in steroidogenic cells. Based on its expression in steroidogenic tissues and DNA-binding specificity, we isolated a putative SF-1 cDNA from an adrenocortical cDNA library. As evidence that this cDNA encodes SF-1, we now show that it is selectively expressed in steroidogenic cells, that an antiserum against its protein product specifically abolishes the SF-1-related gel-shift complex, and that its coexpression increases promoter activity of the 21-hydroxylase 5'-flanking region in transfection experiments. Sequence analyses of the SF-1 cDNA revealed that it is the mouse homolog of fushi tarazu factor I (FTZ-F1), a nuclear receptor that regulates the fushi tarazu homeobox gene in Drosophila. A second FTZ-F1 homolog, embryonal long terminal repeat-binding protein (ELP), was recently isolated from embryonal carcinoma cells. SF-1 and ELP cDNAs are virtually identical for 1017 ba...

/pdf/characterization-of-the-mouse-ftz-f1-gene-which-encodes-a-4e5f1z0zmt.pdf

Edward Kim

Papers

Characterization of the mouse FTZ-F1 gene, which encodes a key regulator of steroid hydroxylase gene expression