Elsevier

Journal of Hepatology

Volume 52, Issue 3, March 2010, Pages 455-462
Journal of Hepatology

Meeting Report
The new therapeutic frontier – Nuclear receptors and the liver

https://doi.org/10.1016/j.jhep.2009.12.002Get rights and content

A joint EASL/AASLD Monothematic Conference on ‘Nuclear Receptors and Liver Disease’ was held from February 27th to March 1st, 2009, in Vienna, Austria, to discuss the latest advances at the forefront of basic and clinical nuclear receptor research and its potential implications for liver diseases. This article reports the highlights of the conference and summarizes the main conclusions emphasizing the relevance for clinical and experimental hepatology. The confluence of nuclear receptors as central transcriptional regulators, acting as sensors and adaptors to many of the small molecules present in the intracellular milieu of all the cells of the liver, provides a current framework to address a broader physiological understanding of the liver. The next stage will be the design and testing of safe and effective therapeutics.

Introduction

The discovery that the largest group of transcriptional regulators in humans – members of the nuclear receptor (NR) superfamily – play strong and pervasive roles in liver cells represents one of the more recent findings in biology that has had a major impact upon our understanding of liver function [1], [2], [3], [4]. This family consists of 48 members in humans, 49 in mice, and >200 in the nematode Caenorhabditis. elegans. NRs are not present in plants or yeast, but are essential components of the functioning of animal cells. These transcriptional regulators are perfectly poised to elaborate responses to their environment and fine-tune the response through various multifunctional regions – N terminal AF1, a DNA-binding Domain (DBD), a Ligand Binding Domain (LBD), and a C Terminal AF2 [5]. Moreover, NRs are targets for post-translational modifications (see below). Such covalent additions to subsets of expressed NR proteins broaden their functionality, both for DNA-binding elements and for interactions with other regulatory proteins. The LBD includes the site for ligand binding and thus is the seat of agonist or antagonist action, the focus of therapeutic targeting. What has recently been determined is that a large number of biologically relevant small molecules that are handled or pass through the liver are actually minute-to-minute regulators of liver function interacting with NRs. With these newly-discovered essential roles for NRs in liver biology and pathobiology in mind, along with the therapeutic consideration for diseases which currently have no effective treatments, the Joint EASL-AASLD Monothematic Conference on Nuclear Receptors and Liver Disease was created. The conference was organized by Michael Trauner (on behalf of EASL) and Saul Karpen (on behalf of AASLD).

From February 27th to March 1st, 2009, 188 participants from 31 countries came to hear 23 speakers and review 72 poster presentations at the Hilton Vienna Conference Center. The purpose and design of this Conference was to identify and convey the newly relevant basic biology of NRs to clinicians and have clinicians reveal opportunities and therapeutic results for NR modulation to basic scientists. This Meeting Report is thus intended to reflect this translational spirit, highlighting themes, unknowns, and opportunities – rather than a strict transcription of the Meeting from start to finish. There were many thoughtful and engrossing personal interactions, new unpublished information, as well as a spirited public give-and-take at the microphones. With this translational future focus in mind, this report will highlight the themes of the Meeting, which was possible only due to the enthusiastic participation of speakers and attendees. We are indebted to all. For those interested in the full list of invited speakers and talk titles, please visit the online site http://www.easl.eu/_events/easl-monothematic-conference/nuclear-receptors-and-liver-disease (also see Supplementary Table 1).

The first NR identified was the estrogen receptor (ER), by Elwood Jensen in 1958, while the Evans’ group cloned the first NR (the glucocorticoid receptor) in 1985 [1], [2], [3], [4], [5], [6]. At first, NR family members were considered part of the endocrine family (estrogen, testosterone, aldosterone), but soon it became apparent with newer cloning technologies that there were many more family members, and that for which the actual ligands were typically unidentified. Over a short period of time (some 10–15 years), prior to the Human Genome Project all 48 members of the NR superfamily were identified. What has become clear is that NRs are multifunctional, ligand-activated transcription factors at the heart of many core liver functions – intermediary metabolism, detoxification, energetics, adaptive response, and bile formation (Fig. 1) to name a few [7], [8], [9]. Several dozen NRs are expressed in liver [10], [11], some of which are cell-specific (e.g., hepatocyte vs. cholangiocyte), while others are expressed by non-parenchymal cells yet crucial for inflammatory and fibrotic response (see below). All together, these multifunctional proteins, each containing a variety of domains to interact with a diverse array of intracellular protein partners and small molecule ligands, provide an understanding of how the liver is at the metabolic, adaptive, inflammatory, and nutritional crossroads of the body.

In addition to the 48 NRs, there are some 200–300 co-regulators (Fig. 2) that contribute to the 50–100 proteins that comprise the transcription complex at each gene. Many of these complex participants have a transient presence or post-translational modifying roles – thus drastically revising and increasing the complexity of the initial model of NRs as DNA-binding proteins whose sole function was to direct recruitment of RNA polymerase activity and thus RNA synthesis [12], [13], [14]. The function of each regulator protein, NR, and co-regulator are broadened by post-translational modifications (e.g., phosphorylation, ubiquitination, sumoylation, methylation, acetylation, etc.), thereby creating tissue, cell, time, and gene-specific effects for various NRs and ligands [15]. This flexibility is central to the adaptive capabilities of the liver to respond to various components of the diet, effect drug metabolism, and integrate responses to injury and regeneration.

NRs play critical roles in liver biology and pathobiology (see Fig. 1, Fig. 2). As a group they are arguably the most important integrators of external signals to core metabolic functions in the body. Many of these NRs function as heterodimer partners with retinoid X receptor (RXR) (Fig. 2), adding another NR participant for regulatory fine-tuning [16]. For example, fats, bile acids, drugs, and food-derived toxins all present themselves to hepatocytes where they can act as ligands (agonists/antagonists) for RXR-containing NR heterodimer pairs, driving gene expression to properly respond. When overloaded (e.g., with select toxins, or excess dietary lipid), the sampling of intracellular content to the NR LBD will thus provide a means to respond. Likewise, antagonists will impair such a response. The role of NRs is not only restricted to responding to external molecules, but is also dictated by inherent circadian and feeding time rhythms that affect NR expression, leading to differential consequences of various diets and drugs, depending upon the time of administration. David Moore presented intriguing new data supporting altered responses of NRs to restricted feeding, altered feeding schedules, and endogenous circadian clocks. More is likely needed to fully flesh out these important concepts when it comes to food and drug delivery [17]. This new concept is likely to have ramifications on our patients regarding drug efficacy, metabolism and toxicity.

Section snippets

Take home messages

  • The liver utilizes many NR superfamily members for core functions.

  • These functions include intermediary metabolism, drug detoxification, lipid metabolism, inflammation, and bile formation.

  • NRs are comprised of multiple domains that provide the perfect “molecular niche” to drive the expression of groups of genes to properly respond to the hepatic environment, providing opportunities for ligand-directed responses.

  • These domains include: activating and protein–protein interacting domains; a ligand

The role of genetics – NR polymorphisms

Given the role of NRs in liver biology, and the need for these to work well despite a wide variety of metabolic demands, it is becoming evident that inter-individual differences in responses to diet and various stressors may very well be encoded in genetic polymorphisms in NR genes. For basic liver biological processes, these have not been fully investigated, but are starting to be identified for FXR, PXR, LXR, VDR, and a few others as outlined by Gerd Kullak-Ublick and Frank Lammert. For

Take home messages

  • With the advent of personalized genomics, more NR polymorphisms will be uncovered that link to disease pathogenesis (e.g., PBC) and altered metabolism (e.g., PXR).

  • GWAS already identified links of NRs to gallstone disease and dyslipidemias. Further analyses on broader populations will help verify these findings and may provide support for NR polymorphisms in various liver pathologies.

  • Correlation of PXR polymorphisms to individualized responses to rifampicin, a PXR agonist, may underlie

Fatty liver disease

Fatty liver disease due to obesity, alcohol or insulin resistance, as part of the metabolic syndrome, is emerging as the pre-eminent liver disease and clinical challenge of the 21st century. A number of NRs have been identified as key regulators of fatty acid (FA) fluxes from peripheral white adipose tissue (WAT) to the liver and hepatic lipid metabolism, by controlling adipogenesis, lipid uptake, de novo lipogenesis, storage, lipolysis, oxidation and export [27], [28]. Surprisingly little is

Take home messages

  • WAT expandability (under the control of NRs such as PPARγ) may be a critical determinant of FA flux to the liver.

  • PPARs regulate lipogenesis (γ) and β-oxidation (α) and are therefore major players in pathogenesis and treatment of NAFLD.

  • Fibroblast growth factors (FGFs) have been identified as novel NR-regulated signals of the nutritional status (FXR- FGF15/19 – fed state; PPARα- FGF21 – fasting response).

  • Bile acids act as enterohepatic hormone fine-tuning hepatic lipid and glucose metabolism via

Cholestasis

As summarized by John Chiang, Gerd Kullak-Ublick and Gernot Zollner, NRs control several steps in hepatic synthesis, metabolism and transport of bile acids and other biliary constituents. In addition to genetic NR variants as susceptibility factors or cofactors in the pathogenesis and/or progression of cholestasis (e.g., FXR–ICP; PXR–PSC) (see above), NRs may help to understand many of the secondary, sometimes adaptive changes in cholestasis as attempt to counteract cholestatic liver injury [44]

Take home messages

  • NR genetic variants can determine the susceptibility to and progression of cholestatic liver disease.

  • NRs mediate secondary and adaptive changes of hepatobiliary transport and metabolism to cholestasis which can be further regulated by NR ligands as therapeutic agents.

  • NRs (e.g., ER) regulate bile duct proliferation in benign and malignant disease states.

Viral hepatitis

As outlined by Patrice Andre, hepatitis B and C virus may be viewed as ’metaboloviruses’ which have a narrow tropism restricted mainly to the liver with specific metabolic pathways as essential factors for viral replication. According to the concept of a ‘metabolovirus’ model, the regulation of HBV and HCV transcription is modulated by nutritional signals. As such, bile acids (as enterohepatic signal via FXR) have been implicated in the metabolic regulation of HCV and HBV replication [46], [47]

Take home messages

  • NRs impact on HBV and HCV replication.

  • Future antiviral strategies may take advantage of NR effects on viral replication.

Liver fibrosis

A range of NRs (PPARγ, FXR, CAR, VDR) may be involved in determining the activation state of hepatic stellate cells (HSC) as key cell type responsible for the fibrogenic response as nicely reviewed by Massimo Pinzani. PPARγ inhibits AP-1 and profibrogenic gene expression in quiescent HSC, while activation of HSC results in loss of PPARγ inhibition, paralleled by vitamin A loss and reduced RAR/RXR expression [48], [49], [50]. Ligands for a range of NRs (e.g., PPARγ, PXR) may have direct

Take home messages

  • NRs control critical steps in hepatic stellate cell activation.

  • NR ligands directed towards stellate cells and myofibroblasts may have direct antifibrotic and anti-inflammatory activities.

Liver regeneration and cancer

With liver cancer rates rising throughout the world, and new roles for NRs in cell cycle and cell transformation in place, it is not surprising that certain NRs are linked to growth/regeneration pathways and liver cancer. Li Wang presented some exceptional data detailing epigenetic regulation of SHP expression and growth of liver cancers, specifically related to SHP promoter region methylation status [40]. These studies provide evidence not only for strong regulation of cell cycle genes by SHP,

Take home messages

  • The strong links between intermediary metabolism and ability to regenerate rest with certain NRs – e.g., FXR, SHP.

  • These same pathways, when aberrantly regulated, can also lead to hepatocellular carcinoma.

  • Xenobiotic NR expression (e.g., CAR) has been linked to human hepatocellular carcinoma.

Drug development and ongoing clinical trials

As outlined by Keith Lindor, Saul Karpen, and Michael Trauner NRs represent attractive drug targets for the treatment of a wide spectrum of liver diseases and their complications since NRs are key regulators of multiple hepatic processes ranging from bile formation, metabolism of endo- and xenobiotics such as bile acids and drugs, over hepatic glucose and lipid metabolism to modulation of liver regeneration, replication of hepatotrophic viruses, hepatic inflammation, fibrogenesis and

Take home messages

  • Several drugs already in everyday clinical use are NR ligands.

  • Specifically designed NR ligands for cholestatic and fatty liver disease are currently in phase II studies.

  • The future may bring more gene and tissue NR specific modulators targeting hepatic bile acid and lipid metabolism, inflammation, fibrosis, cellular proliferation and viral replication.

Summary and outlook

One of the goals of this Monothematic Conference was to identify new avenues of inquiry focused upon understanding, and utilizing, the multiple roles for NRs in liver biology and pathobiology. Such a goal, much less a Conference, could not have been organized 10 years ago, and an initial one was organized by AASLD in Airlie, Virginia in 2003. The timing for this Conference is such as to take advantage of the veritable explosion of new, relevant, and previously unexpected information that place

Acknowledgements

S.J.K. receives research support from NIH. M.T. has received research support from Falk Foundation and Intercept, lecture fees from Falk Foundation, Gilead, Roche, Schering-Plough and has acted as advisor for Gilead and Phenex. The authors and organizers thank all speakers and chairpersons for their vibrant participation and excellent contributions: Domenico Alvaro, Patrice Andre, Johan Auwerx, Ulrich Beuers, John Chiang, Frank Gonzalez, Hinrich Gronemeyer, Steven Kliewer, Gerd Kullak-Ublick,

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