Trends in Biochemical Sciences
ReviewFXR, a multipurpose nuclear receptor
Introduction
In 1995, Forman et al. [1] and Seol et al. [2] isolated a novel cDNA that encoded an ‘orphan’ nuclear receptor. At the time it was named the farnesoid X receptor (FXR) on the basis of its weak activation by farnesol and juvenile hormone III [1], and it has been subsequently classified as NR1H4. There are two known FXR genes, which are commonly referred to as Fxrα and Fxrβ.
Fxrα is conserved from humans to fish (teleost fish, Fugu rubripes) [3]. The single Fxrα gene in humans and mice encodes four FXRα isoforms (FXRα1, FXRα2, FXRα3 and FXRα4) as a result of the use of different promoters and alternative splicing of the RNA 4, 5 (Figure 1a,b). FXRα3 and FXRα4 possess an extended N terminus, which encompasses the poorly defined ‘activation function 1 domain’. In addition, FXRα1 and FXRα3 have an insert of four amino acids (MYTG) immediately adjacent to the DNA-binding domain in a region referred to as the ‘hinge domain’ (Figure 1b). Many FXR target genes are regulated in an isoform-independent manner; however, a few genes, including those encoding intestinal bile acid binding protein (IBABP), syndecan-1, αA-crystallin and fibroblast growth factor 19 (FGF19), are more responsive to the FXRα2 and FXRα4 isoforms lacking the MYTG motif than to FXRα1 and FXRα3 5, 6, 7 (Table 1). Nonetheless, the physiological importance of gene activation by specific FXR isoforms remains to be established. FXRα is expressed mainly in the liver, intestine, kidney and adrenal gland, with much lower levels in adipose tissue 1, 4, 5. Like many other non-steroid hormone nuclear receptors, FXRα binds to specific DNA response elements as a heterodimeric complex with the retinoid X receptor 8, 9 (Figure 1c).
The second FXR gene, Fxrβ, encodes a functional member of the nuclear receptor family in rodents, rabbits and dogs, but is a pseudogene in human and primates [8]. FXRβ has been proposed to be a lanosterol sensor, although its physiological function remains unclear.
In 1999, specific bile acids were identified that both bind to the ligand-binding domain of FXRα and potently activate the transcription of FXRα target genes 10, 11, 12. These effects were noted at micromolar concentrations of bile acids. Because serum contains similar concentrations of bile acids, these studies demonstrated for the first time that bile acids function as hormones. Subsequent studies led to the identification of potent synthetic FXRα agonists including GW4064 [13] and fexaramine [14], compounds such as AGN34 that function as gene-selective agonists or antagonists depending on the target gene [15], and natural compounds such as guggulsterone that function as FXRα antagonists [16]. The mechanism of gene activation that follows binding of these agonists to the ligand-binding domain of FXRα is beyond the scope of this review.
In addition to activating FXR, bile acids have several other functions including (i) facilitation of lipid and fat-soluble vitamin absorption; (ii) activation of three other nuclear receptors, the pregnane X receptor (PXR) [17], the vitamin D receptor [18] and the constitutive androstane receptor (CAR) 19, 20; (iii) activation of the c-Jun N-terminal kinase (JNK) cascade 21, 22; (iv) regulation of the mitogen-activated protein kinase pathway [23]; and (v) activation of TGR5, a G-protein-coupled receptor [24]. Watanabe et al. [25] recently discovered a particularly exciting connection between bile acids, TGR5 and obesity. They demonstrated that administration of cholic acid to mice results in resistance to diet-induced obesity owing to activation of TGR5 in brown adipose tissue, induction of uncoupling protein 1, and enhanced energy expenditure. Despite these many intriguing properties of bile acids, in this review we focus on FXRα, a nuclear receptor that is sometimes called the ‘bile acid receptor’.
The generation of mice deficient in Fxrα (hereafter referred to as Fxr) [26], the identification of FXR target genes, and the availability of synthetic FXR-specific agonists 13, 14, 15 have provided important insights into the mechanisms by which this nuclear receptor controls many diverse metabolic pathways. There are several excellent reviews on bile acid synthesis and metabolism and on FXR 9, 27, 28, 29. Here, we focus specifically on recent developments in our understanding of the regulatory role of FXR in bile acid synthesis, lipoprotein metabolism, liver regeneration, glucose metabolism, protection from hepatotoxic agents, and repression of bacterial overgrowth in the intestine.
Section snippets
FXR and bile acid metabolism
Catabolism of cholesterol to bile acids and their subsequent excretion in the feces is the body's principal means of eliminating cholesterol. Bile acid synthesis is restricted to hepatocytes and occurs via two distinct pathways: the ‘classic’ or neutral pathway, and the ‘alternative’ or acidic pathway [29]. Once synthesized, bile acids are conjugated to amino acids (taurine or glycine) before being secreted into the bile canaliculi (Figure 2). Bile acids, cholesterol, phospholipids and small
FXR, lipoprotein metabolism and atherosclerosis
In the early 1970s, individuals affected with gallstones were orally treated with chenodeoxycholic acid, which it was hoped would enhance the concentration of bile acids in the bile and thus slowly ‘solubilize’ the cholesterol-rich stones. Unexpectedly, this treatment led to a reduction in plasma triglyceride levels both in individuals suffering from gallstones and in those with hypertriglyceridemia 52, 53. The molecular mechanism underlying the hypotriglyceridemic effect of orally administered
FXR and glucose homeostasis
Several studies have linked the regulation of carbohydrate metabolism to FXR 64, 65, 66, 67, 68. Indeed, one report concluded that activation of FXR results in the induction of phosphoenolpyruvate carboxykinase (PEPCK) expression and an increase in glucose output from primary hepatocytes, but does not affect plasma glucose levels in wild-type mice [67]. However, three recent reports have now provided direct evidence that activation of FXR in wild-type or diabetic db/db or KKA-(y) mice promotes
FXR and the control of intestinal bacterial growth
Interruption of bile flow by bile duct ligation or disease results in bacterial proliferation in the small intestine and bacterial translocation. Notably, these effects are attenuated in rats after the oral administration of bile acids 72, 73. Recently, Inagaki et al. [74] provided an explanation for this protective effect of bile acids by demonstrating that intestinal FXR has a crucial role in limiting bacterial overgrowth and thus protecting the intestine from bacterial damage.
Inagaki et al.
FXR and hepatoprotection
Bile acids are physiologically important owing to their detergent-like properties that facilitate lipid absorption; however, these same properties render bile acids highly cytotoxic when their blood or cellular levels increase as a result of disease. Studies in rat models of intrahepatic and extrahepatic cholestasis have demonstrated that activation of FXR by the synthetic agonist GW4064 provides protection against cholestatic liver damage [42]. This FXR-dependent hepatoprotection has been
FXR and liver regeneration
Liver, at least in rodents, shows a remarkable ability to regenerate after the removal of up to 75% of the organ. A recent study by Huang et al. [85] has demonstrated that FXR is important in the liver regeneration process. They found that administration of dietary cholic acid to mice that have undergone partial hepatectomy results in accelerated regeneration and this effect is greatly attenuated in Fxr−/− mice [85]. Because expression of the transcription factor FoxM1b and its downstream
FXR in the kidney and adrenal gland
Although FXR is known to be expressed at high levels in the mouse adrenal cortex 1, 4, 5, the site of active steroidogenesis, its functional role in the adrenal gland remains an enigma. Unlike their presence in the liver, intestine and kidney, bile acids have not been found to flux through the adrenal gland in a physiologically important way. Thus, an alternative possibility for activation of FXR is that the adrenal gland synthesizes its own unique FXR agonist. Indeed, Howard et al. [86] have
Concluding remarks
The initial cloning of FXR in 1995 and the subsequent demonstration that bile acids function as endogenous agonists in 1999 have resulted in an amazing period of discovery. The findings that bile acids, by activating FXR, regulate many diverse metabolic pathways were unexpected. These pathways affect plasma levels of lipids and glucose, hepatic regeneration, hepatoprotection, gallstone production and bacterial growth in the intestine. Taken together, these findings in animals suggest that the
Acknowledgements
Space limitations have precluded the inclusion of many appropriate publications and we apologize to those authors. This work was supported by grants from the National Institutes of Health (grants HL30568 and HL68445) and a grant from Laubisch Fund (P.A.E.), a Beginning Grant-in-aid from American Heart Association (0565173Y to Y.Z.).
References (88)
Identification of a nuclear receptor that is activated by farnesol metabolites
Cell
(1995)Generation of multiple farnesoid-X-receptor isoforms through the use of alternative promoters
Gene
(2002)Natural structural variants of the nuclear receptor farnesoid X receptor affect transcriptional activation
J. Biol. Chem.
(2003)α-Crystallin is a target gene of the farnesoid X-activated receptor in human livers
J. Biol. Chem.
(2005)FXR regulates organic solute transporters α and β in the adrenal gland, kidney, and intestine
J. Lipid Res.
(2006)BAREing it all: the adoption of LXR and FXR and their roles in lipid homeostasis
J. Lipid Res.
(2002)Endogenous bile acids are ligands for the nuclear receptor FXR/BAR
Mol. Cell
(1999)A chemical, genetic, and structural analysis of the nuclear bile acid receptor FXR
Mol. Cell
(2003)Identification of gene-selective modulators of the bile acid receptor FXR
J. Biol. Chem.
(2003)Complementary roles of farnesoid X receptor, pregnane X receptor, and constitutive androstane receptor in protection against bile acid toxicity
J. Biol. Chem.
(2003)
The constitutive androstane receptor and pregnane X receptor function coordinately to prevent bile acid-induced hepatotoxicity
J. Biol. Chem.
Down-regulation of cholesterol 7α-hydroxylase (CYP7A1) gene expression by bile acids in primary rat hepatocytes is mediated by the c-Jun N-terminal kinase pathway
J. Biol. Chem.
Regulation of cholesterol-7α-hydroxylase: BAREly missing a SHP
J. Lipid Res.
The negative effects of bile acids and tumor necrosis factor-α on the transcription of cholesterol 7α-hydroxylase gene (CYP7A1) converge to hepatic nuclear factor-4: a novel mechanism of feedback regulation of bile acid synthesis mediated by nuclear receptors
J. Biol. Chem.
A G-protein-coupled receptor responsive to bile acids
J. Biol. Chem.
Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis
Cell
Regulation of cholesterol 7α-hydroxylase gene (CYP7A1) transcription by the liver orphan receptor (LXRα)
Gene
A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis
Mol. Cell
Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors
Mol. Cell
Loss of nuclear receptor SHP impairs but does not eliminate negative feedback regulation of bile acid synthesis
Dev. Cell
Redundant pathways for negative feedback regulation of bile acid production
Dev. Cell
Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis
Cell Metab.
Elevated cholesterol metabolism and bile acid synthesis in mice lacking membrane tyrosine kinase receptor FGFR4
J. Biol. Chem.
Human bile salt export pump promoter is transactivated by the farnesoid X receptor/bile acid receptor
J. Biol. Chem.
Regulation of multidrug resistance-associated protein 2 (ABCC2) by the nuclear receptors pregnane X receptor, farnesoid X-activated receptor, and constitutive androstane receptor
J. Biol. Chem.
Farnesoid X receptor activates transcription of the phospholipid pump MDR3
J. Biol. Chem.
The orphan nuclear receptor, Shp, mediates bile acid-induced inhibition of the rat bile acid transporter
Ntcp. Gastroenterology
Identification of a bile acid-responsive element in the human ileal bile acid-binding protein gene. Involvement of the farnesoid X receptor/9-cis-retinoic acid receptor heterodimer
J. Biol. Chem.
The heteromeric organic solute transporter α–β, Ostα–Ostβ, is an ileal basolateral bile acid transporter
J. Biol. Chem.
FXR induces the UGT2B4 enzyme in hepatocytes: a potential mechanism of negative feedback control of FXR activity
Gastroenterology
Farnesoid X receptor regulates bile acid–amino acid conjugation
J. Biol. Chem.
Dehydroepiandrosterone sulfotransferase gene induction by bile acid activated farnesoid X receptor
J. Biol. Chem.
Triglyceride-lowering effect of chenodeoxycholic acid in patients with endogenous hypertriglyceridaemia
Lancet
The farnesoid X-receptor is an essential regulator of cholesterol homeostasis
J. Biol. Chem.
A role for FXR and human FGF-19 in the repression of paraoxonase-1 gene expression by bile acids
J. Lipid Res.
Bile acid reduces the secretion of very low density lipoprotein by repressing microsomal triglyceride transfer protein gene expression mediated by hepatocyte nuclear factor-4
J. Biol. Chem.
Loss of functional farnesoid X receptor increases atherosclerotic lesions in apolipoprotein E-deficient mice
J. Lipid Res.
Transient impairment of the adaptive response to fasting in FXR-deficient mice
FEBS Lett.
Coordinated control of cholesterol catabolism to bile acids and of gluconeogenesis via a novel mechanism of transcription regulation linked to the fasted-to-fed cycle
J. Biol. Chem.
Bile acids regulate gluconeogenic gene expression via small heterodimer partner-mediated repression of hepatocyte nuclear factor 4 and Foxo1
J. Biol. Chem.
The farnesoid X receptor modulates adiposity and peripheral insulin sensitivity in mice
J. Biol. Chem.
Oral bile acids reduce bacterial overgrowth, bacterial translocation, and endotoxemia in cirrhotic rats
Hepatology
Pregnane x receptor is a target of farnesoid x receptor
J. Biol. Chem.
Progressive familial intrahepatic cholestasis, type 1, is associated with decreased farnesoid X receptor activity
Gastroenterology
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Authors contributed equally to this review.