ReviewNuclear receptor regulation of hepatic function
Introduction
The hepatocyte is responsible for a great portion of the body's metabolic needs including the synthesis and control of pathways involved in cholesterol, fatty acid, carbohydrate, amino acid, serum protein synthesis, bile acids, and the metabolism/detoxification of drugs and xenobiotics. Any attempt to classify these functions into practical groups may miss certain functions, but leads one to appreciate the vast variety of molecules, signals, toxins and functions that all reside simultaneously within each hepatocyte. It is not surprising that the hepatocyte employs multiple layers of regulation in order to perform its functions, and possesses self-protective processes in order to not to destroy itself in the process of handling a large variety of potentially toxic products at relatively high concentrations. One of the more intriguing, and increasingly appreciated, means of hepatic self-regulation is provided by members of the nuclear receptor (NR) superfamily. The activity of these multipartite transcriptional regulators are themselves controlled by the intracellular concentration of specific ligands, many of which are products shuttled about hepatocytes in the course of performing integrated metabolic functions. Thus, nuclear receptors are the ideal candidates to respond to the complex and ever-changing intracellular environment of the hepatocyte, where they can alter the expression of target genes in order to provide the appropriate physiological response in a timely fashion. It is the purpose of this review to attempt to provide an overview of how select members of the NR superfamily act as sensors and regulators in the expression of a wide variety of metabolically-important target hepatic genes, and why these pathways are relevant for the practicing hepatologist and their patients with liver disease.
Nuclear receptors are being increasingly appreciated by hepatic researchers in virtually all disciplines that affect hepatocyte function – including transport, toxicology, pharmacology, metabolism, nutrition, and physiology. Given the breadth of gene regulation by NRs, it is not possible to cover all aspects in this review (see recent review series in the Journal of Biological Chemistry [1]). Rather, I will focus upon recent studies on how specific ligands and NR family members affect basic hepatic functioning, thereby emphasizing the role of eight of the 48 human NR family members (see Fig. 1 and Table 1) [2]. This should not be interpreted that Type I or homodimer-forming, receptors (glucocorticoid, estrogen, androgen, mineralocorticoid, progesterone), nor other Type II, RXR-heterodimer dependent receptors (e.g. vitamin D, thyroid, PPARγ), nor the monomeric receptors (HNF4, COUP-TF), have insignificant roles in hepatic gene regulation; rather that a detailed discussion is beyond the scope of this review [3], [4]. Also excluded from this review will be a discussion of the important roles of NRs on non-parenchymal liver cell function, even though it is clear that resident hepatic macrophages, and stellate cells are themselves regulated by nuclear receptors and ligands [5], [6], [7], [8]. Finally, the reader is referred to several excellent recent reviews in order to gain a deeper understanding the critical role of co-activators and co-repressors in mediating NR function [9], [10], [11], [12], [13].
Section snippets
Nuclear receptors: general overview and basic concepts
In order to better understand the roles and functions of NRs, a few definitions and clarifications may be helpful. There are over 150 known members of the NR superfamily, the general organization has been evolutionarily conserved for millions of years, and NRs are present in all eukaryotic cells. In humans, 48 members of the NR family have been definitively cloned and identified, while detailed analyses of the available sequences from the Human Genome Project may have uncovered a 49th plus
RXRα
The nuclear receptor RXR (retinoid X receptor) was identified in 1990 by Mangelsdorf et al. in a search for additional retinoid receptors by employing low-stringency screening of human liver cDNA libraries with a human retinoic acid receptor α (RARα) DNA-binding domain cDNA probe [28]. There are three family members (RXRα, RXRβ, RXRγ), each of which utilizes 9-cis retinoic acid (9cRA) as a high affinity ligand [29], [30]. RXRα (NR1B1) is most highly expressed in liver, with lesser but
CAR
The nuclear receptor CAR (constitutive androstane receptor, NR1I3) was identified in, 1994 in a screen for nuclear receptor family members [59]. An obligate RXR partner, CAR is emerging as an important regulator of drug, xenobiotic and bilirubin metabolism, and therefore has a central position in hepatocyte functioning. Its developmental expression pattern is unknown, but it is highly expressed in liver in at least two isoforms [60]. There are several RXR:CAR DNA response elements – DR3, DR4,
FXR
Considerable interest and enthusiasm for incorporating the farnesol X receptor (FXR; NR1H4) into the corps of key hepatic gene regulators came in 1999 when three groups reported that bile acids were high affinity ligands for FXR [85], [86], [87]. Although initially named for its low level response to farnesol, it was clear that the true ligand remained to be determined [88]. The prototypical RXR:FXR response element is an IR1, although some authors recently report IR0 and ER8 RXR:FXR binding
LXR
The liver X receptor (LXR) was discovered in 1995 as part of a screen for liver-enriched NR family members, and has become recently recognized as an important regulator of whole-body cholesterol metabolism [121]. There are two distinct gene products, LXRα (NR1H3) and LXRβ (NR1H2), with diverse patterns of expression, but similar target DNA-binding elements and ligands. LXRα is expressed predominantly in liver, kidney, intestine, fat, adrenal, spleen and in macrophages, while LXRβ is relatively
PPARα
It has been known for over 30 years that select substances can lead to massive proliferation of peroxisomes, including the hypolipidemic fibrates (e.g. clofibrate, ciprofibrate, fenofibrate) [148]. Several substances lead to peroxisomal proliferation including very long chain fatty acids, phthalates, suggesting a common controlling metabolic mechanism. The first peroxisomal proliferator activator receptor (PPAR) was identified in, 1990, and soon thereafter other family members, PPAR(β)δ and
PXR/SXR
The pregnane X receptor (PXR) and steroid and xenobiotic receptor (SXR) were discovered by several groups in, 1998 and soon determined to be rodent (PXR) and human (SXR) versions of the same gene (NR1I2) with significantly distinct ligand affinities [182], [183], [184]. The term PXR/SXR will connote common features of both gene products, while attributes of the human and non-human forms will be discussed individually. PXR/SXR is expressed at high levels in liver and intestine and is a master
RAR
The first retinoic acid receptor, RARα, was identified in 1987 by two groups [210], [211]. Two other receptors, RARβ and RARγ were soon discovered, and each of these have complex tissue and developmental expression patterns [212], [213], [214]. RARα (NR1B1) is the most prevalent isoform in liver and hepatocytes. The endogenous high affinity ligand ATRA, which endogenously is also a source for 9cRA, thereby complicating the interpretation of using ATRA in early experimental studies. A synthetic
SHP
Over the past 2 years, an orphan NR with substantial transcriptional regulatory properties, yet without a DNA-binding domain, has emerged as a central responder to counteract to elevated intracellular bile acid levels. The orphan NR small heterodimer partner (SHP, NR0B2) was identified in 1996 during a screen for NR family members [235]. Its structure revealed a dimerization domain and LBD, but no DBD. SHP appears to repress the function of other NRs by several mechanisms, including
Integration of NR regulation of physiological processes within the liver
The expansive array of ligands, target genes, and metabolic processes regulated by NRs within hepatocytes, and the ever-changing internal milieu, makes a completely comprehensive regulatory scheme virtually impossible to depict graphically. What is apparent is that many of the regulatory ligands are themselves substrates for the target enzymes they induce, and that there is considerable crosstalk among ligands and pathways. Two examples which highlight how multiple NRs coordinate hepatic
Relevance of nuclear receptors for the practicing hepatologist
Given the broad range of processes within the liver under NR control, and their responses to a variety of drugs/toxins and disease states, it should be apparent that a working knowledge of these pathways has relevance to practitioners caring for patients with liver disease (Table 3). In our daily practice, we prescribe drugs that are known or potential NR ligands (e.g. steroids, rifampin, UDCA), deal with the consequences of cholestasis, yet are virtually unable to medically halt the
Acknowledgments
A review of this nature cannot include all references and I apologize for the many important references that have been excluded. David D. Moore's sharing of unpublished information is gratefully acknowledged as well as the continued interest, enthusiasm, and comments of the Karpen laboratory.
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