Review
FXR, a multipurpose nuclear receptor

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The farnesoid X receptor (FXR) is a ligand-activated transcription factor and a member of the nuclear receptor superfamily. In the past six years, remarkable inroads have been made into determining the functional importance of FXR. This receptor has been shown to have crucial roles in controlling bile acid homeostasis, lipoprotein and glucose metabolism, hepatic regeneration, intestinal bacterial growth and the response to hepatotoxins. Thus, the development of FXR agonists might prove useful for the treatment of diabetes, cholesterol gallstones, and hepatic and intestinal toxicity.

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.).

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