Nuclear Receptors in Metabolism



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Introduction to Nuclear Receptors in Metabolism

The steroid and thyroid hormone superfamily of receptors are proteins that are bi-functional, capable of binding hormone as well as directly activating gene transcription. Because these receptors bind ligand intracellularly and then interact with DNA directly they are more commonly called the nuclear receptors (NRs). The steroid/thyroid hormone receptor superfamily includes many members but particular attention in this discussion is placed on the peroxisome proliferator-activated receptors (PPARs), the farnesoid X receptors (FXRs) and the liver X receptors (LXRs) because they all exhibit critical functions in the regulation of metabolic processes. This page serves only as an entry portal to the discussion of the role of these receptors in metabolism. In the sections below is a very brief introduction to each of these three classes of receptor. Each section contains a link to the page describing each class in much more detail. The following Table is not a complete listing of all the identified NRs but is only intended to supply the nomenclature for the NRs important in metabolic regulation as well as those that are mentioned throughout The Medical Biochemistry Page.

 

 

 

 

 

 

 

 

 

 

 


Receptor Nomenclature Receptor Common Name Human Gene Name
Type 1A: Thyroid Hormone Receptors
NR1A1 thyroid hormone receptor-α THRA
NR1A2 thyroid hormone receptor-β THRB
Type 1B: Retinoic Acid Receptors (RAR)
NR1B1 retinoic acid receptor-α (RARα) RARA
NR1B2 retinoic acid receptor-β (RARβ) RARB
NR1B3 retinoic acid receptor-γ (RARγ) RARG
Type 1C: Peroxisome Proliferator-Activated Receptors (PPAR)
NR1C1 peroxisome proliferator-activated receptor-α (PPARα) PPARA
NR1C2 peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) PPARD
NR1C3 peroxisome proliferator-activated receptor-γ (PPARγ) PPARG
Type 1F: RAR-Related Orphan Receptors
NR1F1 RAR-related orphan receptor-α RORA
NR1F2 RAR-related orphan receptor-β RORB
NR1F3 RAR-related orphan receptor-γ RORC
Type 1H: Liver X Receptor-Like Receptors
NR1H2 liver X receptor-β (LXRβ) NR1H2
NR1H3 liver X receptor-α (LXRα) NR1H3
NR1H4 farnesoid X receptor (FXR) NR1H4
NR1H5 farnesoid X receptor-β (FXRβ) NR1H5P
Type 1I: Vitamin D Receptor-Like Receptors
NR1I1 vitamin D receptor (VDR) VDR
NR1I2 pregnane X receptor (PXR) NR1I2
NR1I3 constitutive androstane receptor (CAR) NR1I3
Type 2A: Hepatocyte Nuclear Factor-4 (HNF4) Receptors
NR2A1 hepatocyte nuclear factor-4-α (HNF-4α) HNF4A
NR2A2 hepatocyte nuclear factor-4-γ (HNF-4γ) HNF4G
Type 2B: Retinoid X Receptors (RXR)
NR2B1 retinoid X receptor-α (RXRα) RXRA
NR2B2 retinoid X receptor-β (RXRβ) RXRB
NR2B3 retinoid X receptor-γ (RXRγ) RXRG
Type 0B: DAX-Like Receptors
NR0B1 DAX1 NR0B1
NR0B2 small heterodimer partner, SHP NR0B2

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PPARs: The PPAR family is composed of three family members: PPARα, PPARβ/δ, and PPARγ. Each of these receptors forms a heterodimer with the retinoid X receptors, RXRs (another member of the stereoid/thyroid hormone receptor superfamily). For more detailed information on the PPARs visit the PPAR page.

The first family member identified was PPARα and it was found by virtue of it binding to the fibrate class of anti-hyperlipidemic drugs and resulting in the proliferation of peroxisomes in hepatocytes, hence the derivation of the name of the protein. Although PPARγ and PPARδ are related to PPARα they do not stimulate peroxisome proliferation. Subsequently it was shown that PPARα is the endogenous receptor for polyunsaturated fatty acids. PPARα is highly expressed in the liver, skeletal muscle, heart, and kidney. Its function in the liver is to induce hepatic peroxisomal fatty acid oxidation during periods of fasting. Expression of PPARα is also seen in macrophage foam cells and vascular endothelium. Its role in these cells is thought to be the activation of anti-inflammatory and anti-atherogenic effects.

PPARγ is a master regulator of adipogenesis and is most abundantly expressed in adipose tissue. Low levels of expression are also observed in liver and skeletal muscle. PPARγ was identified as the target of the thiazolidinedione (TZD) class of insulin-sensitizing drugs. The mechanism of action of the TZDs is a function of the activation of PPARγ activity and the consequent activation of adipocytes leading to increased fat storage and secretion of insulin-sensitizing adipocytokines such as adiponectin.

PPARδ is expressed in most tissues and is involved in the promotion of mitochondrial fatty acid oxidation, energy consumption, and thermogenesis. PPARδ serves as the receptor for polyunsaturated fatty acids and VLDLs. Current pharmacologic targeting of PPARδ is aimed at increasing HDL levels in humans since experiments in animals have shown that increased PPARδ levels result in increased HDL and reduced levels of serum triglycerides.

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FXRs: The FXRs are the farnesoid X receptors. For more detailed information on the FXRs visit the FXR page. There are two genes encoding FXRs identified as FXRα and FXRβ. In humans at least four FXR isoforms have been identified as being derived from the FXRα gene as a result of activation from different promoters and the use of alternative splicing; FXRα1, FXRα2, FXRα3, and FXRα4. The FXR gene is also known as the NR1H4 gene (for nuclear receptor subfamily 1, group H, member 4). The FXR genes are expressed at highest levels in the intestine and liver. FXR forms a heterodimer with members of the RXR family. Following heterodimer formation the complex binds to specific sequences in target genes resulting in regulated expression. One major target of FXR is the small heterodimer partner (SHP) gene. Activation of SHP expression by FXR results in inhibition of transcription of SHP target genes. Of significance to bile acid synthesis, SHP represses the expression of the cholesterol 7α-hydroxylase gene (CYP7A1). CYP7A1 is the rate-limiting enzyme in the synthesis of bile acids from cholesterol. The FXRs were originally identified by their ability to bind farensol metabolites. However, subsequent research has demonstrated that FXRs are receptors for bile acids which is the primary mechanism by which bile acids negatively regulate their own expression. In addition to binding bile acids, FXRs have been shown to bind polyunsaturated fatty acids (PUFAs) such as the omega-3 PUFAs docosahexaenoic acid (DHA) and α-linolenic acid (ALA). Most recently, FXR has been shown to bind the androgen hormone, androsterone, derived via testosterone metabolism.

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LXRs: The LXRs are the liver X receptors. For more detailed information on the LXRs visit the LXR page.There are two forms of the LXRs: LXRα and LXRβ. The LXRs form heterodimers with the RXRs and as such can regulate gene expression either upon binding oxysterols (e.g. 22R-hydroxycholesterol) or 9-cis-retinoic acid. Because the LXRs bind oxysterols they are important in the regulation of whole body cholesterol levels. The function of LXRs in the liver is to mediate cholesterol metabolism by inducing the expression of SREBP-1c. SREBP-1c is a transcription factor involved in the control of the expression of numerous genes including several involved in cholesterol synthesis.

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Michael W King, PhD | © 1996–2017 themedicalbiochemistrypage.org, LLC | info @ themedicalbiochemistrypage.org

Last modified: January 22, 2015