FXR and PXR: Potential therapeutic targets in cholestasis

doi:10.1016/j.jsbmb.2011.06.012

The Journal of Steroid Biochemistry and Molecular Biology

Volume 130, Issues 3–5, July 2012, Pages 147-158

https://doi.org/10.1016/j.jsbmb.2011.06.012 Get rights and content

Abstract

Cholestatic liver disorders encompass hepatobiliary diseases of diverse etiologies characterized by the accumulation of bile acids, bilirubin and cholesterol as the result of impaired secretion of bile. Members of the nuclear receptor (NR) family of ligand-modulated transcription factors are implicated in the adaptive response to cholestasis. NRs coordinately regulate bile acid and phospholipid transporter genes required for hepatobiliary transport, as well as the phases I and II metabolizing enzymes involved in processing of their substrates. In this review we will focus on FXR and PXR, two members of the NR family whose activities are regulated by bile acids. In addition, we also discuss the potential of pharmacological modulators of these receptors as novel therapies for cholestatic disorders.

Introduction

Cholestatic liver disorders include a spectrum of hepatobiliary diseases of diverse etiologies that are characterized by impaired hepatocellular secretion of bile, resulting in accumulation of bile acids, bilirubin and cholesterol. Causes of cholestasis include extrahepatic biliary obstruction (e.g. stones, tumors, biliary atresia), intrahepatic biliary obstruction (e.g. primary biliary cirrhosis, primary sclerosing cholangitis) and intrahepatic cholestasis (e.g. drugs, genetic transporter defects, or infections) [1], [2]. In patients with cholestasis, the major abnormalities observed are an elevation of circulating levels of primary bile acids and an increase in the formation of sulfated bile acids. The major mechanism for bile acid elimination in severely cholestatic patients is renal excretion, with the relatively hydrophilic tetrahydroxy bile acids found in their urine [3]. In advanced cholestasis, the ratio of cholic acid (CA) to chenodeoxycholic acid (CDCA) increases in the serum, the proportion of unconjugated bile acids is reduced, and concentrations of the secondary bile acid deoxycholic acid (DCA) decreases [4]. The physiological consequences of reduced intestinal bile acids include maldigestion of fat and malabsorption of fat-soluble vitamins. In addition, increased circulating bile acids may contribute to pruritis [4], as well as apoptosis or necrosis of hepatocytes [5]. Progressive hepatic fibrosis and cirrhosis can ensue leading to death due to hepatic failure or the complications of portal hypertension.

Hepatobiliary transport of bile acids and phospholipids is mediated by specific transporters expressed at the canalicular membrane of the hepatocyte. Impaired function of these transporters leads to reduced bile formation or cholestasis and mutations in these genes are associated with a variety of hereditary cholestatic syndromes. At the transcriptional level, these transporters and the phases I and II metabolizing enzymes involved in processing of their substrates are coordinately regulated by members of the nuclear receptor (NR) family of ligand-modulated transcription factors. In this review, we will focus on FXR and PXR, two members of the NR family whose activities are regulated by bile acids and which are implicated in the adaptive response to cholestasis.

Section snippets

FXR (farnesoid X receptor)

FXR (farnesoid X receptor, NR1H4, also known as bile acid receptor, BAR) was the first nuclear receptor identified to have bile acids as endogenous and physiologically relevant ligands [6], [9]. FXR serves as a sensor for bile acids and promotes enterohepatic clearance of bile acids by controlling the expression of genes involved in their transport and metabolism. In addition, FXR counteracts liver X receptor (LXR) in both cholesterol and triglyceride metabolism [7]. FXR is abundantly expressed

Regulation of bile acid transport and metabolism by FXR

Activation of FXR in vivo is associated with increased hepatobiliary circulation of bile acids, inhibition of hepatic bile acid biosynthesis, and a reduction in plasma triglycerides [25]. Below we will discuss the roles of FXR in bile acid transport and metabolism and the implications for cholestatic disorders (Fig. 2).

PXR (pregnane X receptor)

PXR (NR1I2, also known as the steroid and xenobiotic receptor (SXR) or the pregnane-activated receptor (PAR)), is a promiscuous nuclear receptor that is activated by structurally unrelated xenobiotics, steroids, drugs and bile acids [95], [96]. In response to a diverse array of compounds, PXR coordinately regulates a suite of genes involved in the metabolism, transport, and ultimately, elimination of these molecules. PXR is highly expressed in the liver, small intestine, and colon [95], [96].

Regulation of bile acid transport and metabolism by PXR

Although PXR was initially characterized as a xenosensor, the discovery that certain bile acids such as LCA can serve as ligands for both human and mouse PXR provided a link between PXR and bile acid regulation [106], [107]. Below we will discuss the role of PXR in the detoxification of bile acids and the implications in cholestatic disorders (Fig. 4).

Implications for cholestatic liver disorders

Pharmacological therapy for cholestasis is limited, and ursodeoxycholic acid (UDCA) is the only disease-modifying drug therapy with evidence of efficacy, improving symptoms, hepatic enzyme abnormalities, and reducing death and liver transplantation in patients with primary biliary cirrhosis (PBC), when commenced sufficiently early in the course of the disease [122], [123], and improving both maternal and fetal outcomes in cholestasis of pregnancy [124]. However, a majority of PBC patients are

FXR agonists

FXR agonists would be expected to provide a positive therapeutic effect where cholestasis is present in the absence of obstruction of large bile ducts. As covered in the preceding section, FXR-mediated up-regulation of apical hepatocyte bile acid transporters and increased bile production is counterproductive when bile cannot be delivered to the intestine. Recently, a potent selective FXR agonist has entered clinical phase II trials for PBC. 6-ethyl CDCA (6-ECDCA) is a modified bile acid with

Future perspectives

Cholestatic liver disorders cover a wide spectrum of diseases of diverse etiologies. However, they all share the consequences of retention of bile constituents, especially bile acids. As covered in this review, the nuclear receptors FXR and PXR are activated by bile acids and in turn regulate aspects of the enterohepatic cycling and metabolism of bile acids. It follows that any disease process in which either of these factors is important could potentially benefit from pharmacological

Acknowledgements

We would like to thank Ann Atkins for critically reading the manuscript and Jamie Simon for help with the artwork. This work was supported by the Human Frontier Science Program (HFSP) (JWJ), Marie Curie Reintegration grant under the 7th Framework Programme of the European Commission (JWJ), National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases Nuclear Receptor Signaling Atlas orphan receptor Grant U19DK62434, the Environmental Protection Agency Superfund

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ReviewFXR and PXR: Potential therapeutic targets in cholestasis☆

Abstract

Introduction

Section snippets

FXR (farnesoid X receptor)

Regulation of bile acid transport and metabolism by FXR

PXR (pregnane X receptor)

Regulation of bile acid transport and metabolism by PXR

Implications for cholestatic liver disorders

FXR agonists

Future perspectives

Acknowledgements

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Cholestatic liver disease: pathophysiology and therapeutic options

Liver

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J. Pharmacol. Exp. Ther.

Identification of a nuclear receptor for bile acids

Science

LXRS and FXR: the yin and yang of cholesterol and fat metabolism

Annu. Rev. Physiol.

Review
FXR and PXR: Potential therapeutic targets in cholestasis☆