[Frontiers in Bioscience 14, 4904-4920, June 1, 2009]
Hepatobiliary ABC transporters: physiology, regulation and implications for disease
Johan W. Jonker 1, Catherine A.M. Stedman2, Christopher Liddle3, Michael Downes1
1
TABLE OF CONTENTS
1. ABSTRACT
The liver plays a key role in the metabolic conversion and elimination of endo- and xenobiotics. Hepatobiliary transport of many of these compounds is mediated by several ATP-binding cassette (ABC) transporters expressed at the canalicular membrane of the hepatocyte. Impaired function of these ABC transporters leads to impaired bile formation or cholestasis and mutations in these genes are associated with a variety of hereditary cholestatic syndromes. At the transcriptional level, these ABC transporters and the 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 ABC transporters involved in hepatobiliary excretion and how they are associated with hepatic physiology and disease states. We will also examine how NRs, acting as intracellular sensors for lipophilic molecules, regulate these ABC transporters and maintain metabolic homeostasis.
2. INTRODUCTION
The body is continuously exposed to a wide variety of environmental chemicals (xenobiotics), endogenously synthesized compounds (endobiotics) and metabolic waste products arising from the metabolism of both sources of molecules. The liver plays a central role in their elimination and is equipped with a plethora of detoxification mechanisms. Central to this detoxification are the processes of metabolism and transport, both of which are carried out by superfamilies of specialized proteins the members of which exhibit substrate specificity. Hepatocytes, the most abundant cells in the liver, are polarized epithelial cells with a basolateral (sinusoidal) membrane facing the blood and an apical (canalicular) membrane facing the bile canaliculus (Figure 1). Hepatic uptake is initiated at the basolateral membrane, which is in direct contact with portal blood plasma via the fenestrae of the sinusoidal endothelial cells and the space of Disse. After uptake into hepatocytes, bile acids and other cholephiles reach the canalicular membrane by diffusion either in the aqueous cytoplasm or within intracellular lipid membranes, depending on their hydrophobicity. The canalicular membrane represents the excretory pole of the hepatocyte and forms the border of the bile canaliculus (Figure 2). Canalicular excretion of biliary constituents is the rate-limiting step of bile formation since biliary constituents are excreted against high concentration gradients into bile. The basolateral and canalicular membranes differ in their biochemical composition and functional characteristics and are separated by tight junctions that seal off the bile canaliculi and hence form the only anatomical barrier maintaining the concentration gradient between blood and bile (1). The primary functions of bile are firstly, to act as a detergent for the emulsification of dietary lipids and lipid-soluble vitamins, thereby promoting their intestinal absorption; and secondly, the removal of endobiotics, xenobiotics and their metabolites. The main constituents of normal bile are bile acids (72% of solutes by weight), phospholipids (24%) and cholesterol (4%) (2). Each component is actively excreted into bile by specific ABC transporters expressed at the canalicular membrane and defects in these transporters have been associated with distinct clinical syndromes. Bile acids, which combined with phospholipids form mixed micelles and provide the detergent properties of bile, are conserved through extensive entero-hepatic recirculation. From the total bile acid pool in adult humans (3-4 g), only 1 to 2% per day is lost through fecal excretion and this loss is compensated by de novo bile acid synthesis from cholesterol in the liver (3). Hepatic re-uptake of bile acids at the sinusoidal membrane is mediated by the sodium-dependent bile acid uptake system NTCP (SLC10A1) and by several members of the organic anion transporting polypeptide (OATP) family that facilitate sodiumindependent bile acid uptake (4). Within the hepatocyte, the majority of bile acids are bound to cytosolic proteins and traverse the cell by diffusion. At the canalicular membrane, active transport of bile acids results in canalicular bile acid concentrations that are about 100- to 1000-fold higher than in portal blood (3). This strong osmotic gradient attracts water and provides the driving force for bile flow. Impaired transport of bile acids or phospholipids will compromise bile flow and consequently lead to cholestasis.
Besides its role in digestion, bile also serves as a major excretory route for many endobiotics, such as cholesterol and the heme catabolite bilirubin, which like bile acids and phospholipids have specialized ABC transporters mediating their excretion. In addition, there are several polyspecific ABC transporters which have a broad substrate specificity and act as "vacuum cleaners" to eliminate a wide range of compounds, particularly xenobiotics such as therapeutic drugs. Altered expression of a subset of canalicular transporters can potentially impact on the pharmacokinetics and therefore the efficacy and toxicity of a broad range of medications. In this review we will focus on hepatocyte apical ABC transporters involved in biliary excretion and how they are associated with hepatic physiology and disease states. We will also examine how nuclear receptors, acting as intracellular sensors for lipophilic molecules, regulate these ABC transporters and maintain metabolic homeostasis.
3. HEPATOCYTE APICAL ABC TRANSPORTERS IN PHYSIOLOGY AND DISEASE
3.1. ABCB1 (MDR1/P-glycoprotein)
P-glycoprotein was discovered over 30 years ago by its capacity to confer multidrug resistance (MDR) in a Chinese hamster ovary cell line that was selected for resistance to colchicine (5). It was the first member of what turned out to be a superfamily of ATP-binding cassette (ABC) transport proteins, with 48 members in humans, many of which are associated with disease states (6-8). In 1999, P-glycoprotein was renamed ABCB1 by the Human Genome Nomenclature Committee. Throughout this review we will use the new nomenclature and, where necessary, indicate alternative names for clarity. Ten years after its discovery, it was demonstrated that ABCB1 is encoded by the MDR1 gene, which had been shown independently to be associated with multidrug resistance in cultured cells (9-10). Most of the work on ABCB1 in the two decades after its discovery focused on the characterization of its molecular and biochemical properties and its relevance to chemotherapeutic cytotoxic drug resistance in cells and tumors. ABCB1 is a large (approximately 1280 amino acids), N-glycosylated, membrane-spanning protein that functions as an ATP-driven efflux pump. It is localized in the plasma membrane of the cell, where it can actively extrude a variety of drugs. The polypeptide chain consists of two similar halves, each containing six putative transmembrane segments and an intracellular ATP-binding site. Hydrolysis of ATP provides the energy for active substrate export, which can occur against a large concentration gradient. Its most striking property is its broad substrate specificity for a wide range of structurally and functionally unrelated compounds, including a vast number of drugs covering many therapeutic applications. This broad substrate specificity also explains extensive cross-resistance observed in drug resistant cells and tumors that overexpress ABCB1.
ABCB1 is expressed in a variety of pharmacologically important epithelial barriers, such as the intestinal epithelium, the blood-brain and blood-nerve barrier, the blood-testis barrier, and the materno-fetal barrier formed by placental trophoblasts. ABCB1 is also expressed at the biliary canalicular membrane of hepatocytes and at the brush border of renal proximal tubule cells. The pharmacological and physiological significance of ABCB1, however, remained obscure until Abcb1a knockout mice were created (11). Humans have one gene encoding ABCB1, whereas mice have two genes, Abcb1a (Mdr3, Mdr1a) and Abcb1b (Mdr1, Mdr1b). The tissue distribution of mouse Abcb1a and Abcb1b suggests that together they fulfil the same function as ABCB1 in humans. Although, Abcb1 knockout mice were viable and fertile and at first appeared phenotypically normal, a serendipitous event provided the first insight into one of its major functions. When these mice were treated with a topical spray of the anti-parasitic ivermectin, a routine procedure to treat mite infestation, almost all the knockout mice died whereas wild-type mice were unaffected (11). Further analysis revealed that the mice had died of neurotoxicity due to dramatically increased brain penetration of ivermectin. It turned out that Abcb1a has an important function in the blood-brain barrier. Abcb1a, expressed in luminal membrane (i.e. facing the blood) of the endothelial cells of small capillaries, prevents the entry of substrate drugs into the brain by actively pumping them back into the circulation. Absence of Abcb1a from the blood-brain barrier, can lead to up to 10- to 100-fold increased brain penetration of substrate drugs, thus turning normally harmless agents like ivermectin into lethal neurotoxins. Interestingly, a deletion mutation of the ABCB1 gene was also shown to be responsible for the ivermectin sensitivity of a subpopulation of collie dogs (12). A few years later, Sparreboom et al. (13) were the first to demonstrate role of ABCB1 in limiting oral bioavailability and mediating biliary excretion of drugs. After intravenous or oral administration, plasma levels of the anticancer drug paclitaxel were 2- and 6-fold increased in Abcb1 knockout mice as compared to wild-type mice, respectively. This increase was due to a combination of increased intestinal absorption and decreased elimination into bile. The precise role of ABCB1 in direct intestinal excretion and biliary transport was further elucidated in mice with a cannulated gallbladder allowing repeated bile sampling (13-15). Studies using Abcb1 knockout mice have also demonstrated a protective role in a variety of other tissues and barriers including the materno-fetal barrier, blood-testis barrier and bone marrow (16). It has now become clear that ABCB1 is a key player in the defense of the body against xenotoxins with the result that the main focus of ABCB1 research has shifted from its role in drug resistant cancer to its pharmacological functions.
3.2. ABCB4 (MDR2/3 P-glycoprotein)
The search for additional proteins that could confer multidrug resistance independently led to the isolation of a gene highly homologous to ABCB1 in two laboratories, and was named MDR2 and MDR3, respectively (17-18). Nomenclature for this gene has been extremely confusing as rodents have two genes encoding MDR1 P-glycoprotein (Abcb1), one of which was originally also named Mdr3. For clarity, these genes have later been renamed to Mdr1a (Mdr3) and Mdr1b (Mdr1) and ultimately to Abcb1a and Abcb1b. Mdr2 in rodents is the ortholog of human MDR2/3 and is now officially renamed ABCB4. ABCB4 is expressed in a variety of tissues including liver, heart, skeletal muscle and B lymphocytes (18-19). However, unlike ABCB1, ABCB4 was not involved in conferring the MDR phenotype and its function remained unknown for several years until knockout mice were generated (20). Abcb4 knockout mice displayed progressive liver damage at an early age, which was accompanied by hyperbilirubinemia and increased liver enzymes in plasma. Further analysis revealed the absence of phospholipids and dramatically reduced levels of cholesterol and glutathione in bile, whereas bile flow itself was about 2-fold increased (20). A link with a human disease was made when De Vree et al. (21) showed that ABCB4 is mutated in patients with progressive familial intrahepatic cholestasis type 3 (PFIC3), a subgroup of PFIC characterized by reduced or absent phospholipid excretion into bile and increased serum levels of γGT. Later it was established that ABCB4 functions as a phospholipid flippase, promoting the transfer of phosphatidylcholine from the inner to the outer leaflet of the plasma membrane lipid bilayer (22). Phospholipids are essential constituent of the bile and act to reduce the detergent activity of bile acid micelles, thereby protecting the membranes of cells lining the biliary tree from damage. In the absence of phospholipids, bile acid toxicity results in damage to cholangiocytes and progressive cholestatic liver injury accompanied by increased serum levels of γGT, as seen in PFIC-3.
3.3. ABCB11 (BSEP/S-PGP)
By low stringency screening for novel proteins that might confer MDR, another close homolog of P-glycoprotein was identified and named sister of P-glycoprotein (s-Pgp) (23). The function of s-Pgp, which was later renamed ABCB11, remained unknown until Gerloff et al. (24) demonstrated that it represents the hepatocyte canalicular bile salt export pump (BSEP). Based on the earlier observation by Nishida et al. (25), that transport of bile acids is ATP-dependent, Gerloff et al. (24) demonstrated transport of bile acids by ABCB11 in vitro, using cRNA injected Xenopus laevis oocytes and vesicles isolated from transfected Sf9 cells (24). Shortly thereafter, the human ortholog was cloned and found to be mutated in progressive familial intrahepatic cholestasis type 2 (PFIC2) (26). PFIC2 is an autosomal recessive disorder characterized by early onset intrahepatic cholestasis, jaundice, pruritus and progression to hepatic fibrosis, cirrhosis and endstage liver disease before adulthood. PFIC2 patients exhibit a 100-fold reduction in bile acid secretion into bile resulting in the accumulation of bile acids within hepatocytes, liver injury and cholestasis. Unlike patients with PFIC3 (see � 3.2.), serum levels of cholesterol and γGT are usually normal or only mildly elevated. Mutations in ABCB11 have also been associated with two milder cholestatic syndromes: 1) benign recurrent intrahepatic cholestasis type 2 (BRIC2), which is characterized by intermittent episodes of cholestasis without progression to liver disease and 2) intrahepatic cholestasis of pregnancy (ICP), which is associated with increased risk of intrauterine fetal death and prematurity (27-28). Although the functional consequences of most mutations in ABCB11 are still unknown, several mutations have been demonstrated to result in impaired activity, stability or trafficking to the membrane (29-30). The severity of the different cholestatic phenotypes has further been demonstrated to correlate with activity and levels of expression of ABCB11 (31). In contrast to humans with PFIC2, targeted inactivation of Abcb11 in mice resulted only in a mild non-progressive cholestasis (32). Surprisingly, although secretion of cholic acid (CA), the major bile acid in mice, was greatly reduced (to 6% of wild-type), total bile acid output in mutant mice was still about 30% of wild-type. Also, secretion of an unexpectedly large amount of tetrahydroxylated bile acids, which were not present in wild-type mice, was observed. These results suggested that hydroxylation and an alternative canalicular transport mechanism for bile acids could compensate for the absence of Abcb11 and protect the mutant mice from severe cholestatic liver injury (33). Abcb11 knockout mice fed with a diet supplemented with CA displayed a more severe PFIC2 phenotype, indicating that with bile acid loading this compensatory transport was not sufficient (33). Further analysis of the Abcb11 knockout mice showed that expression of Abcb1 (Mdr1) was markedly increased, especially after CA feeding, while Abcb4 (Mdr2), Abcc2 (Mrp2), and Abcc3 (Mrp3) were increased only to a moderate extent (34). Moreover, plasma membrane vesicles isolated from a cell line overexpressing ABCB1 exhibited ATP-dependent bile salt transport, albeit with a 5-fold lower affinity compared to ABCB11. These findings suggested that, in mice Abcb1 may act as a compensatory bile acid transporter, and could explain the relatively mild phenotype of Abcb11 knockout mice (34). In keeping with the more severe phenotype in humans, no upregulation of ABCB1 was found in PFIC2 patients (35). In addition to its role in PFIC2, Abcb11 has been mapped to the Lith1 locus for gallstone susceptibility in mice (36). Interestingly, the Lith1 locus also harbors the nuclear receptor LXRα, which is associated with gallstone formation through the regulation of cholesterol transport by ABCG5/8 (see � 3.5.). The role of Abcb11 in the formation of gallstones was confirmed by the finding that gallstone-susceptible C57L/J mice (Lith1 mice) displayed increased levels of Abcb11 as compared to gallstone-resistant AKR/J mice (37-38) and further by the fact that transgenic mice overexpressing hepatic Abcb11 rapidly developed cholesterol gallstones (39).
3.4. ABCC2 (MRP2/cMOAT)
ABCC2 (previously known as MRP2 or canalicular multispecific organic anion transporter (cMOAT)) was independently identified in two laboratories based on its similarity with ABCC1 and absence of its expression in homozygous MRP2-deficient rats and humans (40-41). The in vivo function of ABCC2 was elucidated prior to identification of its encoding gene, as ABCC2 is effectively deficient in two mutant rat strains (TR−/GY and EHBR), and in patients that suffer from the Dubin-Johnson syndrome (42-46). Affected individuals suffer from a recessively inherited conjugated hyperbilirubinemia, which can result in clinically apparent jaundice, but overall the phenotype of this disease is relatively mild. The cause of the defect is the absence of ABCC2, from the hepatocyte canalicular membrane, where it normally mediates the hepatobiliary excretion of (amongst others) mono- and bis-glucuronidated bilirubin. Although many mutations in the ABCC2 gene have been identified, only some of them result in Dubin-Johnson syndrome. ABCC2 expression is highest in the canalicular membrane of the liver, but it is also expressed in the kidney, jejunum, and ileum, where it may also be involved in the elimination of toxic compounds from the body (47). Recently, Abcc2 knockout mice have been generated (48-50). These mice display hyperbilirubinemia and reduced levels of biliary glutathione but the overall phenotype is relatively mild as compared to humans and rats.
3.5. ABCG5/ABCG8 (Sterolin 1 and 2)
ABCG5 and ABCG8 have been identified as the major sterol transporters (51-53). ABCG5 and -8 are half-transporters, primarily expressed in liver and intestine, where they function as an obligate heterodimer to limit the intestinal absorption and promote biliary excretion of dietary sterols. In this way, they provide the body with a mechanism to selectively limit systemic exposure to plant sterols while allowing absorption and retention of cholesterol. Mutations in these genes are associated with sitosterolemia (also known as phytosterolemia), a rare autosomal recessive disorder characterized by elevated plasma and tissue levels of plant sterols, xanthomatosis and increased risk for atherosclerosis (54). Disruption of Abcg5/8 in mice resulted in a 2- to 3-fold increase in fractional absorption of dietary plant sterols, and was associated with a 30-fold increase in plasma sitosterol (55). The accumulation of plant sterols in Abcg5/8 null mice was further associated with an overall decrease in cholesterol production and secretion (55-56). This altered cholesterol homeostasis is suggested to be mediated by two critical regulatory pathways; first, via activation of LXR by selective plant sterols such as stigmasterol, resulting in increased elimination of cholesterol through upregulation of the cholesterol transporter ABCA1, and second, via inhibition of de novo cholesterol synthesis (56). Conversely, genetic overexpression or pharmacological induction of ABCG5/8 through LXR activation resulted in increased cholesterol secretion and reduced absorption (57-58). By quantitative trait locus (QTL) and genome wide SNP analysis, ABCG5/8 have also been linked to the formation of cholesterol gallstones in mice and humans, respectively (59-62). In humans, gallstone risk was specifically attributable to a G-to-C transversion corresponding to an Asp19His (D19H) substitution in the ABCG8 gene (61-62). These findings suggest that D19H is a gain of function mutation resulting increased efficiency of cholesterol transport into the bile lumen, causing cholesterol hypersaturation of bile and promoting the formation of gallstones. This is in line with previous studies suggesting that this D19H variant results in increased ABCG8 activity (63-64).
3.6. ABCG2 (BCRP/MXR/ABCP)
Besides ABCB1 (MDR1) and ABCC1 (MRP1), ABCG2 was the third transporter found to confer multidrug resistance (MDR), and together they account for most if not all MDR activity observed in cell lines. The ABCG2 gene was first cloned based on its overexpression in a highly doxorubicin-resistant MCF-7 breast cancer cell line (65-66). Despite reported expression in a variety of tumors, its role in clinical drug resistance is still unclear (67). ABCG2 is a half-transporter that functions as a homodimer in the plasma membranes of a variety of mostly epithelial cells (68). ABCG2 is present at strategic sites in the body, such as the intestine, placenta and blood-brain barrier, where it protects the organism by limiting the systemic and tissue penetration and hence toxicity of xenotoxins. In addition, ABCG2 is strongly induced in the mammary gland during lactation where it is responsible for the active secretion of substrates into milk (69-70). The in vivo function of ABCG2 was first illustrated by pharmacological inhibition of ABCG2 in mice, demonstrating its role in limiting oral absorption, mediating biliary excretion and fetal protection (71-72). ABCG2 has also been shown to be expressed in hematopoietic and many other stem cells, where it may have a protective function, or play a role in maintaining progenitor cells in an undifferentiated state (73-74). ABCG2 can transport a structurally and functionally diverse range of organic substrates, including hydrophobic compounds, weak bases, organic anions, and glucuronide-, sulfate-, glutamylate- and glutathione-conjugates of many endogenous and exogenous molecules. Abcg2 knockout mice have been generated independently in two laboratories (75-76) being viable and healthy but displaying an extreme sensitivity to the dietary chlorophyll breakdown product pheophorbide A, resulting in severe, sometimes lethal phototoxic lesions on light-exposed skin (75). Abcg2 knockout mice also display a unique type of porphyria, not caused by a defect in one of the enzymes of the heme biosynthetic pathway, in contrast to the typical hereditary porphyrias (75). Porphyrias are metabolic disorders characterized by increased intracellular levels of porphyrins, the precursors of heme, and a subset are associated with skin photosensitivity in affected patients (77). In addition, one of the hallmarks of erythropoietic protoporphyria (EPP) is the deposition of protoporphyrin IX (PPIX) in the liver, causing progressive and sometimes fatal liver damage (78). PPIX can only be removed from the liver via biliary excretion and recently ABCG2-mediated transport of conjugated PPIX has been implicated in this process (79). In this way, ABCG2 is believed to function as an overflow system, allowing the liver to eliminate excess PPIX by high-affinity transport of its conjugates, thereby preventing or reducing its cytotoxicity.
4. REGULATION OF HEPATIC TRANSPORT AND METABOLISM BY NUCLEAR RECEPTORS
4.1. Nuclear Receptors
The Nuclear Receptor (NR) superfamily is comprised of 48 individual transcription factors that serve as pleiotropic and prototypic regulators of cellular differentiation and function. This stems in part from their ability to function as ligand-dependent sensors for steroid hormones, fat soluble hormones and metabolic intermediates, as well as dietary lipids. NRs are widely implicated in disease states and encompass one of the most successful therapeutically and pharmacologically validated drug targets. NRs bind to sequence-specific DNA response elements on target gene promoters as homodimers, heterodimers, or monomers. Structural and functional analyses of the NR superfamily have demonstrated that the receptors are comprised of functional modular domains (80) (Figure 3). A highly variable N-terminal region contains a ligand-independent activation domain called AF-1. The central DNA-binding domain (DBD), consisting of two highly conserved zinc-finger motifs unique to NRs, targets the receptor to specific DNA sequences called hormone response elements (HRE). A typical HRE consists of two hexa-nucleotide motifs AGGTCA or its variants, separated by a gap of several nucleotides. Binding specificity by various receptors is largely achieved by the spacing (the 3-4-5 rule) and the orientation of two half-sites (direct-, inverted- or everted-repeat). The hinge region confers structural flexibility in the receptor dimers allowing a single receptor dimer to interact with multiple HRE sequences. The C-terminal ligand-binding domain (LBD) is functionally very unique to NRs and responsible for ligand recognition, receptor dimerization and cofactor interaction.
Through recent extensive NR-expression profiling studies we now know a great deal about the spatial and temporal expression profiles for the 49 murine NRs (81-82). Of interest to this review, it was found that a large number of the NR family members are expressed in the liver and gut, 37 and 41 respectively. Eight NRs are effectively limited in expression to these tissues, including the farnesoid X receptor (FXR, NR1H4), liver receptor homolog-1 (LRH-1, NR5A2), small heterodimer partner (SHP, NR0B2), hepatocyte nuclear factor-4α and -γ (HNF-4α,γ NR2A1,2), the vitamin D receptor (VDR, NR1I1), pregnane X receptor (PXR, NR1I2), and constitutive androstane receptor (CAR, NR1I3). In addition, liver X receptors (LXRα and β, NR1H3 and 2) are abundant in liver and play an important roles in hepatic cholesterol transport and metabolism. Numerous studies have now demonstrated that NRs play key roles in many of the diverse of signaling and homeostatic processes of the enterohepatic axis including digestion, lipid and energy homeostasis as well as inflammation (83). Perhaps one of the major ways by which NRs achieve this complex regulation is through their ability to regulate at the transcriptional level the synthesis of endobiotics and the degradation and transport of both endobiotic and xenobiotic molecules in the liver.
4.2. Regulation of bile acid transport and metabolism by FXR
Bile acids are endogenous ligands for several NRs that in turn regulate bile acid synthesis, hydroxylation, and transport into and out of the hepatocyte via the basolateral and apical membrane transporters. Specifically, bile acids directly activate FXR, PXR and VDR, with differing ligand specificities for individual bile acids. FXR (also known as BAR, bile acid receptor) was the first NR identified to have bile acids as endogenous and physiologically relevant ligands. FXR is closely related to LXR, and both belong to the NR1H subfamily of NRs (84). FXR is abundantly expressed in the liver and intestine as well as the kidney and adrenal gland (85). Bile acids function as endogenous ligands for FXR, with differing potency. In vitro studies indicate that chenodeoxycholic acid (CDCA) is a potent FXR ligand at physiological concentrations, whereas others such as lithocholic acid (LCA), deoxycholic acid (DCA), and CA are less effective, and muricholic acids do not activate FXR (86-87). Interestingly, although LCA can by itself act as a weakly agonistic ligand for FXR, it strongly antagonizes CDCA-stimulated activation of FXR (88). Synthetic agonists that mimic the ability of bile acids to activate the FXR include the isoxazole derivative GW4064 (89), and fexaramine (90). FXR transcriptionally activates ABCB11 (91-93), and bile acids increase ABCB11 expression in primary hepatocytes or HepG2 cells with the same rank order of potency that activates FXR (94). Conversely, the secondary bile acid LCA decreases ABCB11 expression by antagonizing FXR activation (88). An important mechanism of drug-induced cholestasis is inhibition of ABCB11, with accumulation of bile acids in hepatocytes and subsequent liver injury. Examples of such drugs include cyclosporin A, rifampicin and glibenclamide. Reductions in ABCB11 have also been implicated in sepsis-induced cholestasis (4). Recently, an LRH-1 response element (LRHRE) was identified in the human ABCB11 promoter and overexpression of LRH-1 was shown to induce expression of ABCB11, suggesting that the NR LRH-1 supports FXR in the regulation of bile acid levels (95).
FXR also downregulates many target genes indirectly via transcriptional induction of another NR, small heterodimer partner (SHP, NR0B2) (96-97). SHP is an atypical member of the NR subfamily as it lacks a DNA-binding domain. SHP can interact with and negatively affect the transcriptional activity of several other members of the NR subfamily, including LXR, LRH-1, HNF-4α (Figure 2), as well as transcription factors belonging to the basic-helix-loop-helix family. It appears that SHP-mediated repression involves competition with transcriptional coactivators for access to DNA-bound transcription factors. SHP also contains a strong transcriptional repressor domain in its carboxy-terminus, which may contribute to the SHP-mediated repression (98-99).
4.3. Regulation of bile acid metabolism through CYP7A1
The first and rate-limiting enzyme in the neutral pathway of bile acid biosynthesis is cytochrome P450 7A1 (CYP7A1), a liver-specific microsomal cytochrome P450, catalyzing the formation of 7α-hydroxycholesterol from cholesterol. CYP7A1 regulation is controlled by a variety of factors, including hormones, oxysterols, bile acids, drugs and diurnal rhythms (100). In rodents, LXR binds to a direct repeat NR motif (DR-4) in the Cyp7a1 promoter when activated by oxysterols, and strongly induces Cyp7a1 transcription (101). Interestingly, LXR does not activate human CYP7A1 expression in the same way, which means that humans are more susceptible to developing hypercholesterolemia from a high cholesterol diet than rodents (102). The CYP7A1 proximal promoter also contains a negative bile acid response element (BARE), that can bind two nuclear receptors: monomeric LRH-1, and homodimeric HNF-4α (103-104). PGC-1α is a versatile coactivator for many nuclear receptors, and has been shown to increase the HNF-4α-mediated transactivation of CYP7A1, as well as other genes (105). Bile acids negatively regulate bile acid synthesis via CYP7A1, by several mechanisms. By activating FXR, bile acids induce the expression of SHP, which in turn negatively interacts with LRH-1, and possibly HNF-4α to inhibit the CYP7A1 gene (96). However, bile acids are still able to repress Cyp7a1 expression in SHP knockout mice, suggesting the presence of redundant mechanisms (106). Bile acids can also activate PXR, and recent work has suggested that activated PXR interferes with HNF-4α signaling by competing for PGC-1α in hepatic cells, resulting in dissociation of PGC-1α, and suppression of the CYP7A1 gene (107). Additionally, FXR directly activates the transcription of the fibroblast growth factor 19 (FGF-19) (108) which, via the intracellular JNK (c-Jun N-terminal kinase) pathway, leads to reduced CYP7A1 expression (106).
4.4. Regulation of ABCC2, ABCB4 and ABCG5/8
ABCC2 can transport a variety of compounds including bilirubin diglucuronide, sulfates, some bile acids (e.g. conjugates of LCA), xenobiotics (e.g. cisplatin, anthracyclines, vinca alkaloids, methotrexate), as well as glutathione conjugates into bile, and is therefore a major determinant of bile acid-independent bile flow (109). Once bile acids have been excreted into bile, they stimulate the release of phosphatidylcholine (PC) and cholesterol from the outer leaflet of the canalicular membrane, which then form mixed micelles in bile. By doing so, bile acid toxicity to the bile duct epithelium is avoided, which would otherwise occur due to an unopposed detergent action. It has been suggested that bile acids can regulate ABCC2 expression, since CDCA, an FXR ligand, can induce the expression of ABCC2 mRNA in human and rat hepatocytes (1). An atypical promoter everted repeat element (ER-8) has been identified within the rat Abcc2 promoter that is involved in the ligand-mediated induction of Abcc2 by FXR, PXR and CAR in cultured cells (110). Subsequently, in vivo studies of mice with cholestasis induced by common bile duct ligation have found regulation of Abcc2 to be independent of FXR (111). Induction of Abcc2 in the liver of PXR wild-type but not knockout mice has been reported after administration of pregnenolone 16α-carbonitrile (PCN) or CA (112-113), implying a significant in vivo role for PXR in regulation of Abcc2.
In humans, ABCB4 is induced in cholestasis (114), and is regulated by FXR (115). Trans-activation of ABCB4 by FXR has been demonstrated through direct binding of FXR/retinoid X receptor α (RXRα) heterodimers to a highly conserved inverted repeat element (FXR response element) at the distal promoter (115). In rats, Abcb4 is induced by the FXR agonist GW4064 (116), but can still be induced in FXR knockout mice fed a CA diet (117), suggesting that several bile acid-responsive regulatory mechanisms must be capable of inducing this gene. In mice, another NR, peroxisome-proliferator activated receptor α (PPARα, NR1C1) has also been shown to be involved in Abcb4 regulation (118).
ABCG5 and ABCG8 facilitate biliary removal of neutral sterols, and are coordinately upregulated at the transcriptional level by dietary cholesterol. These genes are direct targets of LXR (119), a NR that regulates the expression of may key genes involved in lipid metabolism and energy homeostasis. Additionally, a binding site for LRH-1 has been identified in the ABCG5/8 intergenic region necessary for the activity of both the ABCG5 and ABCG8 promoters (120).
4.5. Regulation of the multidrug transporters ABCB1 and ABCG2
The transcriptional regulation of ABCB1 is complex, and numerous transcription factors have been implicated in its regulation (121). A large number of drugs have been identified as either substrates or inhibitors of ABCB1, and a range of exogenous stimuli can increase transcription of the Abcb1 promoter (122). Bile acids and their conjugated metabolites are not substrates for ABCB1; however certain substrates for ABCB1, including drugs, may also inhibit ABCB11 if they accumulate in the liver (1). Bile flow remains normal in Abcb1a/b knockout mice, and organic cation excretion is only modestly impaired. In vitro studies have implicated rifampicin- and paclitaxel-mediated activation of PXR in the induction of ABCB1 expression in human colon carcinoma cell lines, and induction of Abcb1b by a range of xenobiotics has also been shown to be dependent on PXR (123-124). However, in a study involving administration of CA to mice, Abcb1a expression was induced independently of PXR and FXR (125), and levothyroxine was demonstrated to upregulate Abcb1 independently of PXR (126), suggesting that induction by endobiotics differs from induction by xenobiotics. More recently, physiological concentrations of bile acids were shown in vivo to induce Abcb1a and Abcb1b via FXR, independently of PXR (127), demonstrating the complexity of in vivo regulation of these transporters.
ABCG2 has been shown to be transcriptionally regulated by the Estrogen Receptor α (ERα, NR3A1). An estrogen response element (ERE) was found in the ABCG2 promoter and 17β-estradiol (E2) enhanced the expression of ABCG2 mRNA in estrogen receptor ER-positive T47D:A18 cells and PA-1 cells stably expressing ERα (128). ABCG2 is abundant in the placenta and is highly induced in the mammary gland during pregnancy suggesting a physiological function for ER in the regulation of ABCG2 in these tissues. Recently, ABCG2 has been shown to be regulated by PPARγ (NR1C3) in human dendritic cells (129). Three PPAR/RXR binding sites were identified upstream of the ABCG2 gene as well as an increased ABCG2 mRNA and protein expression following treatment with the PPARγ agonist rosiglitazone. The physiological function of this PPARγ-dependent upregulation of ABCG2, and whether it is restricted to cells of the myeloid lineage, is not known.
4.6. Implications for cholestatic liver disorders
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), intrahepatic biliary obstruction (e.g. primary biliary cirrhosis, primary sclerosing cholangitis) and intrahepatic cholestasis (e.g. drugs, genetic transporter defects, or infections) (130-131). When there is complete absence of bile flow (as in biliary obstruction), there is an absence of bile acids in the small intestine, an increase in bile acids in the hepatocyte and in plasma, and an increase in the urinary excretion of bile acids. Phospholipids, cholesterol and conjugated bilirubin that were destined for biliary secretion also accumulate in the plasma in cholestasis (132). The major abnormalities in bile acid metabolism in patients with cholestasis are elevation of circulating levels of primary bile acids, increased formation of sulfated bile acids, and a shift to renal excretion as a major mechanism for bile acid elimination. In particular, relatively hydrophilic tetrahydroxy bile acids are formed and excreted in urine. The ratio of the serum concentration of CA to CDCA increases, the proportion of unconjugated bile acids is reduced, and concentrations of the secondary bile acid DCA acid decrease in advanced cholestasis (132). These changes have physiological consequences, with absence of intestinal bile acids resulting in fat maldigestion because of absence of micelle formation, and malabsorption of fat-soluble vitamins. Increased circulating bile acids may cause pruritis (132), and in the hepatocyte are likely to induce apoptosis or necrosis because of their detergent properties (133). Progressive hepatic fibrosis and cirrhosis can ensue leading to death due to hepatic failure or the complications from portal hypertension.
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 (134-135), and improving both maternal and fetal outcomes in cholestasis of pregnancy (136). However a majority of patients are incomplete responders to UDCA (137), and UDCA has not been demonstrated to be efficacious in other forms of cholestasis, such as primary sclerosing cholangitis. There is therefore a need for novel therapies for treatment of cholestasis, both to delay progression of liver disease and relieve associated symptoms. The physiological response to cholestasis generally involves downregulation of the hepatocyte basolateral uptake transporters (114) and upregulation of the basolateral efflux transporters (Donner et al., 2001). Interestingly, the apical transporter function is often preserved. Abcb11 expression is only modestly impaired, or preserved, both in animals with bile duct obstruction (111) and in humans with cholestasis (114, 139). ABCB4 and ABCB1 are both induced in humans with cholestasis (114), suggesting that bile acids that are specific ligands for FXR may help to maintain expression of these transporters during cholestatic injury. NR-mediated regulation has a marked impact on the development of hepatic damage in cholestasis, and this is most clearly demonstrated in NR knockout mice subjected to various models of cholestasis and/or bile acid overload. Mice with deletion of PXR or CAR have an increase in the areas of hepatic necrosis and bile infarcts after injection of LCA (140-141), or bile duct ligation (142). Mechanisms for this include loss of NR-mediated bile acid detoxification mechanisms, encompassing both metabolism and transport. Conversely, PXR activation by PCN protects wild-type mouse livers against necrosis caused by LCA (140-141). Similarly, the FXR knockout phenotype demonstrates altered bile acid and lipid homeostasis (117), and an altered response to various animal models of cholestasis. High concentrations of dietary CA cause a marked increase in serum, liver and urine bile acid concentrations, and severe hepatotoxicity in FXR knockout mice, associated with the loss of expression of Abcb11, and reduced biliary elimination of bile acids (117, 125, 143). However in a bile duct ligation (BDL) model of complete biliary obstruction, FXR knockout mice had a mortality and morbidity advantage, and were protected from developing hepatic bile infarcts, even with concurrent deletion of PXR. This protection is probably secondary to downregulation of the FXR-regulated apical transporters ABCB11, ABCB4 and ABCB1, reducing pressure in obstructed bile ducts, as well as other effects including upregulation of the sinusoidal ABC transporter ABCC4 (MRP4) which mediates transport of bile acids back into the circulation (127, 144). These findings suggest a role for targeted therapy for different cholestatic syndromes, and specifically, a clinical role for FXR antagonists in the treatment of obstructive cholestasis, and PXR agonists in other cholestatic syndromes.
5. PERSPECTIVE
As covered in this review, the apical hepatocyte ABC transporters determine both the composition and flow of bile. It follows that any disease process in which either of these factors is important could potentially benefit from pharmacological manipulation of these transporters. The most obvious disease candidates are the cholestatic liver disorders, as covered in � 4.6. In addition, gallstones, the most common of all biliary diseases, should be largely preventable in high-risk individuals if bile can be manipulated to reduce lithogenicity, particularly lowering of cholesterol content, lowering of deoxycholic acid concentration and maintenance of bile flow (145). Direct manipulation of the transporter proteins to achieve these therapeutic goals is likely to prove difficult. A more tantalizing approach is to target the NRs recognized as being responsible for the regulation of these transporters. Like their classical steroid hormone relatives, certain bile acids and oxysterols are signaling molecules that are sensed by NRs. These in turn regulate multiple aspects of hepatic metabolism and transport as well as contributing to communication between the intestine and the liver to coordinate digestion and energy homeostasis. Using both genetic abrogation as well as pharmacological manipulation in mice, FXR, PXR and CAR have been shown to influence cholestatic liver disease in animal models to the point of significantly impacting on survival after complete bile duct ligation. Given its role in regulating biliary cholesterol transport via ABCG5/8, it is not surprising that LXR activation increases bile lithogenicity causing cholesterol crystallization by increasing cholesterol and phospholipid concentrations while lowering bile acids (146). Given their pharmacological tractability, these and other closely related NRs such as the PPARs are presently of interest for a range of human diseases extending from cholestasis to fatty liver disease through to inflammatory bowel disease (147). Research priorities include the development of additional pharmacologic tools for the manipulation of these receptors and exploration of their effects in a more diverse range of in vivo models, particularly in view of the observed differences between rodents and man in some aspects of transporter regulation. If suitable nuclear receptor agonists and antagonists can be developed early phase human studies are likely to yield exciting results.
Finally, genetic variation in the apical hepatocyte ABC transporters is well recognized and has significant clinical implications. Loss of function mutations can lead to severe cholestatic liver disorders, as observed in PFIC2 and PFIC3. More subtle changes are associated with conditions such as BRIC2 and ICP. It is becoming apparent that variability in these transporters also contributes to gallstone susceptibility (61) and is associated with drug clearance phenotypes (148), however more extensive research is needed to further clarify these associations. An important question is whether genetic variability also contributes to idiosyncratic drug-induced liver disease, a spectrum adverse drug responses that affect the liver, often have a cholestatic component and represent a major issue in therapeutic drug development (149). Again, further studies are needed to determine if this is the case and if these often severe reactions to often commonly used drugs can be predicted and therefore avoided.
6. ACKNOWLEDGEMENT
J.W.J. is supported by the Human Frontier Science Program (HFSP). This work was supported by the National Institutes of Health (HD027183). Jamie Simon is acknowledged for the artwork.
7. REFERENCES
1. M. Trauner, and J.L. Boyer: Bile salt transporters: molecular characterization, function, and regulation. Physiol Rev 83, 633-671 (2003)
2. M.C. Carey, and J.T. Lamont: Cholesterol gallstone formation. 1. Physical-chemistry of bile and biliary lipid secretion. Prog Liver Dis 10, 139-163 (1992)
3. P.J. Meier, and B. Stieger: Bile salt transporters. Annu Rev Physiol 64, 635-661 (2002)
doi:10.1146/annurev.physiol.64.082201.100300
4. G.A. Kullak-Ublick, B. Stieger, and P.J. Meier: Enterohepatic bile salt transporters in normal physiology and liver disease. Gastroenterology 126, 322-342 (2004)
doi:10.1053/j.gastro.2003.06.005
5. R.L. Juliano, and V. Ling: A su rface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim Biophys Acta 455, 152-162 (1976)
doi:10.1016/0005-2736(76)90160-7
6. C.F. Higgins: ABC transporter s: from microorganisms to man. Annu Rev Cell Biol 8, 67-113 (1992)
doi:10.1146/annurev.cb.08.110192.000435
7. M. Dean, Y. Hamon, and G. Chimini: The human ATP-binding cassette (ABC) transporter superfamily. J Lipid Res 42, 1007-1017 (2001)
8. P. Borst, and R. Oude Elferink: Mammalian ABC transporters in health and disease. Annu Rev Biochem 71, 537-592 (2002)
doi:10.1146/annurev.biochem.71.102301.093055
9. Ueda, K., Cornwell, M.M., Gottesman, M.M., Pastan, I., Roninson, I.B., Ling, V., and Riordan, J.R. : The md r1 gene, responsible for multidrug-resistance, codes for P-glycoprotein. Biochem Biophys Res Commun 141, 956-962 (1986)
doi:10.1016/S0006-291X(86)80136-X
10. D.W. Shen, A. Fojo, J.E. Chin, I.B. Roninson, N. Richert, I. Pastan, and M.M. Gottesman: Human multidrug-resistant cell lines: increased mdr1 expression can precede gene amplification. Science 232, 643-645 (1986)
doi:10.1126/science.3457471
11. A.H. Schinkel, J.J. Smit, O. van Tellingen, J.H. Beijnen, E. Wagenaar, L. van Deemter, C.A. Mol, M.A. van der Valk, E.C. Robanus-Maandag, H.P. te Riele, A.J. Berns, and P. Borst: Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell 77, 491-502 (1994)
doi:10.1016/0092-8674(94)90212-7
12. K.L. Mealey, S.A. Bentjen, J.M. Gay, and G.H. Cantor: Ivermectin sensitivity in collies is associated with a deletion mutation of the mdr1 gene. Pharmacogenetics 11, 727-733 (2001)
doi:10.1097/00008571-200111000-00012
13. A. Sparreboom, J. van Asperen, U. Mayer, A.H. Schinkel, J.W. Smit, D.K. Meijer, P. Borst, W.J. Nooijen, J.H. Beijnen, and O. van Tellingen: Limited oral bioavailability and active epithelial excretion of paclitaxel (Taxol) caused by P-glycoprotein in the intestine. Proc Natl Acad Sci USA 94, 2031-2035 (1997)
doi:10.1073/pnas.94.5.2031
14. U. Mayer, E. Wagenaar, J.H. Beijnen, J.W. Smit, D.K. Meijer, J. van Asperen, P. Borst, and A.H. Schinkel: Substantial excretion of digoxin via the intes tinal mucosa and prevention of long-term digoxin accumulation in the brain by the mdr 1a Pglycoprotein. Br J Pharmacol 119, 1038-1044 (1996)
15. J. van Asperen, O. van Tellingen, and J.H. Beijnen: The role of mdr1a P-glycoprotein in the biliary and intestinal secretion of doxorubicin and vinblastine in mice. Drug Metab Dispos 28, 264-267 (2000)
16. A.H. Schinkel, and J.W. Jonker: Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: an overview. Adv Drug Deliv Rev 55, 3-29 (2003)
doi:10.1016/S0169-409X(02)00169-2
17. I.B. Roninson, J.E. Chin, K.G. Choi, P. Gros, D.E. Housman, A. Fojo, D.W. Shen, M.M. Gottesman, and I. Pastan: Isolation of human mdr DNA sequences amplified in multidrug-resistant KB carcino ma cells. Proc Natl Acad Sci USA 83, 4538-4542 (1986)
doi:10.1073/pnas.83.12.4538
18. A.M. van der Bliek, F. Baas, T. ten Houte de Lange, P.M. Kooiman, T. van der Velde-Koerts, and P. Borst: The human mdr3 gene encodes a novel P-glycoprotein homologue and gives rise to alternatively spliced mRNAs in liver. EMBO J 6, 3325-3331 (1987)
19. J.M. Croop, M. Raymond, D. Haber, A. Devault, R.J. Arceci, P. Gros, and D.E. Housman: The three mouse multidrug resistance (mdr) genes are expressed in a tissue-specific manner in normal mouse tissues. Mol Cell Biol 9, 1346-1350 (1989)
20. J.J. Smit, A.H. Schinkel, R.P. Oude Elferink, A.K. Groen, E. Wagenaar, L. van Deemter, C.A. Mol, R. Ottenhoff, N.M. van der Lugt, M.A. van Roon, et al.: Homozygous dis ruption of the murine mdr2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver disease. Cell 75, 451-462 (1993)
doi:10.1016/0092-8674(93)90380-9
21. J.M. de Vree, E. Jacquemin, E. Sturm, D. Cresteil, P.J. Bosma, J. Aten, J.F. Deleuze, M. Desrochers, M. Burdelski, O. Bernard, R.P. Oude Elferink, and M. Hadchouel: Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis. Proc Natl Acad Sci USA 95. 282-287 (1998)
doi:10.1073/pnas.95.1.282
22. A.J. Smith, J.L. Timmermans-Hereijgers, B. Roelofsen, K.W. Wirtz, W.J. van Blitterswijk, J.J. Smit, A.H. Schinkel, and P. Borst: The human MDR3 P-glycoprotein promotes translocation of phosphatidylcholine through the plasma membrane of fibroblasts from transgenic mice. FEBS Lett 354, 263-266 (1994)
doi:10.1016/0014-5793(94)01135-4
23. S. Childs, R.L. Yeh, E. Georges, and V. Ling: Identification of a sister gene to P-glycoprotein. Cancer Res 55, 2029-2034 (1995)
24. T. Gerloff, B. Stieger, B. Hagenbuch, J. Madon, L. Landmann, J. Roth, A.F. Hofmann, and P.J. Meier: The sister of Pglycoprotein represents the canalicular bile salt export pump of mammalian liver. J Biol Chem 273, 10046-10050 (1998)
doi:10.1074/jbc.273.16.10046
25. T. Nishida, Z. Gatmaitan, M. Che, and I.M. Arias: Rat liver canalicular membrane vesicles contain an ATP-dependent bile acid transport system. Proc Natl Acad Sci USA 88, 6590-6594 (1991)
doi:10.1073/pnas.88.15.6590
26. S.S. Strautnieks, L.N. Bull, A.S. Knisely, S.A. Kocoshis, N. Dahl, H. Arnell, E. Sokal, K. Dahan, S. Childs, V. Ling, M.S. Tanner, A.F. Kagalwalla, A. Németh, J. Pawlowska, A. Baker, G. Mieli-Vergani, N.B. Freimer, R.M. Gardiner, and R.J. Thompson: A g ene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis. Nat. Genet. 20, 233-238 (1998)
doi:10.1038/3034
27. S.W. van Mil, W.L. van der Woerd, G. van der Brugge, E. Sturm, P.L. Jansen, L.N. Bull, I.E. van den Berg, R. Berger, R.H. Houwen, and L.W. Klomp: Benign recurrent intrahepatic cholestasis type 2 is caused by mutations in ABCB11. Gastroenterology 127, 379-384 (2004)
doi:10.1053/j.gastro.2004.04.065
28. C. Pauli-Magnus, T. Lang, Y. Meier, T. Zodan-Marin, D. Jung, C. Breymann, R. Zimmermann, S. Kenngott, U. Beuers, C. Reichel, R. Kerb, A. Penger, P.J. Meier, and G.A. Kullak-Ublick: Sequence analysis of bile salt export pump (ABCB11) and multidrug resistance p-glycoprotein 3 (ABCB4, MDR3) in patients with intrahepatic cholestasis of pregnancy. Pharmacogenetics 14, 91-102 (2004)
doi:10.1097/00008571-200402000-00003
29. L. Wang, C.J. Soroka, and J.L. Boyer: The role of bile salt export pump mutations in progressive familial intrahepatic cholestasis type II. J Clin Invest 110, 965-972 (2002)
30. J.R. Plass, O. Mol, J. Heegsma, M. Geuken, J. de Bruin, G. Elling, M. Müller, K.N. Faber, and P.L. Jansen: A progressive familial intrahepatic cholestasis type 2 mutation causes an unstable, temperature-sensitive bile salt export pump. J Hepatol 40, 24-30 (2004)
doi:10.1016/S0168-8278(03)00483-5
31. P. Lam, C.L. Pearson, C. Soroka, S. Xu, A. Mennone, and J.L. Boyer: The Level of Plasma Membrane Expression in Progressive and Benign Mutations of the Bile Salt Export Pump (Bsep/Abcb11) Correlate with Severity of Cholestatic Diseases. Am J Physiol Cell Physiol 293, C1709-16 (2007)
doi:10.1152/ajpcell.00327.2007
32. R. Wang, M. Salem, I.M. Yousef, B. Tuchweber, P. Lam, S.J. Childs, C.D. Helgason, C. Ackerley, M.J. Phillips, and V. Ling: Targeted inactivation of sister of P-glycoprotein gene (spgp) in mice results in nonprogressive but persistent intrahepatic cholestasis. Proc Natl Acad Sci USA 98, 2011-2016 (2001)
doi:10.1073/pnas.031465498
33. R. Wang, P. Lam, L. Liu, D. Forrest, I.M. Yousef, D. Mignault, M.J. Phillips, and V. Ling: Severe cholestasis induced by cholic acid feeding in knockout mice of sister of P-glycoprotein. Hepatology 38, 1489-1499 (2003)
34. P. Lam, R. Wang, and V. Ling: Bile acid transport in sister of P-glycoprotein (ABCB11) knockout mice. Biochemistry 44, 12598-12605 (2005)
doi:10.1021/bi050943e
35. V. Keitel, M. Burdelski, U. Warskulat, T. Kühlkamp, D. Keppler, D. Häussinger, and R. Kubitz: Expression and localization of hepatobiliary transport proteins in progressive familial intrahepatic cholestasis. Hepatology 41, 1160-1172 (2005)
doi:10.1002/hep.20682
36. G. Bouchard, H.M. Nelson, F. Lammert, L.B. Rowe, M.C. Carey, and B. Paigen: High-resolution maps of the murine Chromosome 2 region containing the cholesterol gallstone locus, Lith1. Mamm Genome 10, 1070-1074 (1999)
doi:10.1007/s003359901163
37. D.Q. Wang, B. Paigen, and M.C. Carey: Phenotypic characterization of Lith genes that determine susceptibility to cholesterol cholelithiasis in inbred mice: physical-chemistry of gallbladder bile. J Lipid Res 38, 1395-1411 (1997)
38. F. Hoda, and R.M. Green: Hepatic canalicular membrane transport of bile salt in C57L/J and AKR/J mice: implications for cholesterol gallstone formation. J Membr Biol 196, 9-14 (2003)
doi:10.1007/s00232-003-0620-4
39. A. Henkel, Z. Wei, D.E. Cohen, and R.M. Green: Mice overexpressing hepatic Abcb11 rapidly develop cholesterol gallstones. Mamm Genome 16, 903-908 (2005)
doi:10.1007/s00335-004-2465-2
40. R. Mayer, J. Kartenbeck, M. Büchler, G. Jedlitschky, I. Leier, and D. Keppler: Expression of the MRP gene-encoded conjugate export pump in liver and its selective absence from the canalicular membrane in transport-deficient mutant hepatocytes. J Cell Biol 131, 137-150 (1995)
doi:10.1083/jcb.131.1.137
41. C.C. Paulusma, P.J. Bosma, G.J. Zaman, C.T. Bakker, M. Otter, G.L. Scheffer, R.J. Scheper, P. Borst, and R.P. Oude Elferink: Congenital jaundice in rats with a mutation in a multidrug resistance-associated protein gene. Science 271, 1126-1128 (1996)
doi:10.1126/science.271.5252.1126
42. P.L. Jansen, W.H. Peters, and W.H. Lamers: Hereditary chronic conjugated hyperbilirubinemia in mutant rats caused by defective hepatic anion transport. Hepatology 5, 573-579 (1985)
doi:10.1002/hep.1840050408
43. S. Hosokawa, O. Tagaya, T. Mikami, Y. Nozaki, A. Kawaguchi, K. Yamatsu, and M. Shamoto: A new rat mutant with chronic conjugated hyperbilirubinemia and renal glomerular lesions. Lab Anim Sci 42, 27-34 (1992)
44. K. Ito, H. Suzuki, T. Hirohashi, K. Kume, T. Shimizu, and Y. Sugiyama: Expression of the putative ATP-binding cassette region, homologous to that in multidrug resistance associated protein (MRP), is hereditarily defective in Eisai hyperbilirubinemic rats (EHBR). Int Hepatol Commun 292, 292-299 (1996)
45. G. Jedlitschky, U. Hoffmann, and H.K. Kroemer: Structure and function of the MRP2 (ABCC2) protein and its role in drug disposition. Expert Opin Drug Metab Toxicol 2, 351-366 (2006)
doi:10.1517/17425255.2.3.351
46. A.T. Nies, and D. Keppler: The apical conjugate efflux pump ABCC2 (MRP2). Pflugers Arch 453, 643-659 (2007)
doi:10.1007/s00424-006-0109-y
47. C.G. Dietrich, D.R. de Waart, R. Ottenhoff, I.G. Schoots, and R.P. Elferink: Increased bioavailability of the food-derived carcinogen 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine in MRP2-deficient rats. Mol Pharmacol 59, 974-980 (2001)
48. X.Y. Chu, J.R. Strauss, M.A. Mariano, J. Li, D.J. Newton, X. Cai, R.W. Wang, J. Yabut, D.P. Hartley, D.C. Evans, and R. Evers: Characterization of mice lacking the multidrug resistance protein MRP2 (ABCC2). J Pharmaco. Exp Ther 317, 579-589 (2006)
doi:10.1124/jpet.105.098665
49. M.L. Vlaming, K. Mohrmann, E. Wagenaar, D.R. de Waart, R.P. Elferink, J.S. Lagas, O. van Tellingen, L.D. Vainchtein, H. Rosing, J.H. Beijnen, J.H. Schellens, and A.H. Schinkel: Carcinogen and anticancer drug transport by Mrp2 in vivo: studies using Mrp2 (Abcc2) knockout mice. J Pharmacol Exp Ther 318, 319-327 (2006)
doi:10.1124/jpet.106.101774
50. K. Nezasa, X. Tian, M.K. Zamek-Gliszczynski, N.J. Patel, T.J. Raub, and K.L. Brouwer: Altered hepatobiliary disposition of 5 (and 6)-carboxy-2',7'-dichlorofluorescein in Abcg2 (Bcrp1) and Abcc2 (Mrp2) knockout mice. Drug Metab Dispos 34, 718-723 (2006)
doi:10.1124/dmd.105.007922
51. S.B. Patel, G. Salen, H. Hidaka, P.O. Kwiterovich, A.F. Stalenhoef, T.A. Miettinen, S.M. Grundy, M.H. Lee, J.S. Rubenstein, M.H. Polymeropoulos, and M.J. Brownstein: Mapping a gene involved in regulating dietary cholesterol absorption. The sitosterolemia locus is found at chromosome 2p21. J Clin Invest 102, 1041-1044 (1998)
doi:10.1172/JCI3963
52. K.E. Berge, H. Tian, G.A. Graf, L. Yu, N.V. Grishin, J. Schultz, P. Kwiterovich, B. Shan, R. Barnes, and H.H. Hobbs: Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science 290, 1771-1775 (2000)
doi:10.1126/science.290.5497.1771
53. M.H. Lee, K. Lu, S. Hazard, H. Yu, S. Shulenin, H. Hidaka, H. Kojima, R. Allikmets, N. Sakuma, R. Pegoraro, A.K. Srivastava, G. Salen, M. Dean, and S.B. Patel: Identification of a gene, ABCG5, important in the regulation of dietary cholesterol absorption. Nat Genet 27, 79-83 (2001)
doi:10.1038/87170
54. A.K. Bhattacharyya, and W.E. Connor: Beta-sitosterolemia and xanthomatosis. A newly described lipid storage disease in two sisters. J Clin Invest 53, 1033-1043 (1974)
doi:10.1172/JCI107640
55. L. Yu, R.E. Hammer, J. Li-Hawkins, K. Von Bergmann, D. Lutjohann, J.C. Cohen, and H.H. Hobbs: Disruption of Abcg5 and Abcg8 in mice reveals their crucial role in biliary cholesterol secretion. Proc Natl Acad Sci USA 99, 16237-16242 (2002)
doi:10.1073/pnas.252582399
56. C. Yang, L. Yu, W. Li, F. Xu, J.C. Cohen, and H.H. Hobbs: Disruption of cholesterol homeostasis by plant sterols. J Clin Invest 114, 813-822 (2004)
57. L. Yu, J. Li-Hawkins, R.E. Hammer, K.E. Berge, J.D. Horton, J.C. Cohen, and H.H. Hobbs: Overexpression of ABCG5 and ABCG8 promotes biliary cholesterol secretion and reduces fractional absorption of dietary cholesterol. J Clin Invest 110, 671-680 (2002)
58. L. Yu, J. York, K. von Bergmann, D. Lutjohann, J.C. Cohen, and H.H. Hobbs: Stimulation of cholesterol excretion by the liver X receptor agonist requires ATP-binding cassette transporters G5 and G8. J Biol Chem 278, 15565-15570 (2003)
doi:10.1074/jbc.M301311200
59. H. Wittenburg, M.A. Lyons, R. Li, G.A. Churchill, M.C. Carey, and B. Paigen: FXR and ABCG5/ABCG8 as determinants of cholesterol gallstone formation from quantitative trait locus mapping in mice. Gastroenterology 125, 868-881 (2003)
doi:10.1016/S0016-5085(03)01053-9
60. H. Wittenburg, M.A. Lyons, R. Li, U. Kurtz, J. Mössner, G.A. Churchill, M.C. Carey, and B. Paigen: Association of a lithogenic Abcg5/Abcg8 allele on Chromosome 17 (Lith9) with cholesterol gallstone formation in PERA/EiJ mice. Mamm Genome 16, 495-504 (2005)
doi:10.1007/s00335-005-0006-2
61. S. Buch, C. Schafmayer, H. Völzke, C. Becker, A. Franke, H. von Eller-Eberstein, C. Kluck, I. Bässmann, M. Brosch, F. Lammert, J.F. Miquel, F. Nervi, M. Wittig, D. Rosskopf, B. Timm, C. Höll, M. Seeger, A. ElSharawy, T. Lu, J. Egberts, F. Fändrich, U.R. Fölsch, M. Krawczak, S. Schreiber, P. Nürnberg, J. Tepel, and J. Hampe: A genome-wide association scan identifies the hepatic cholesterol transporter ABCG8 as a susceptibility factor for human gallstone disease. Nat Genet 39, 995-999 (2007)
doi:10.1038/ng2101
62. F. Grünhage, M. Acalovschi, S. Tirziu, M. Walier, T.F. Wienker, A. Ciocan, O. Mosteanu, T. Sauerbruch, and F. Lammert: Increased gallstone risk in humans conferred by common variant of hepatic ATP-binding cassette transporter for cholesterol. Hepatology 46, 793-801 (2007)
doi:10.1002/hep.21847
63. J.A. Hubacek, K.E. Berge, J.C. Cohen, and H.H. Hobbs: Mutations in ATP-cassette binding proteins G5 (ABCG5) and G8 (ABCG8) causing sitosterolemia. Hum Mutat 18, 359-360 (2001)
doi:10.1002/humu.1206
64. K.E. Berge, K. von Bergmann, D. Lutjohann, R. Guerra, S.M. Grundy, H.H. Hobbs, and J.C. Cohen: Heritability of plasma noncholesterol sterols and relationship to DNA sequence polymorphism in ABCG5 and ABCG8. J Lipid Res 43, 486-494 (2002)
65. L.A. Doyle, W. Yang, L.V. Abruzzo, T. Krogmann, Y. Gao, A.K. Rishi, and D.D. Ross: A multidrug resistance transporter from human MCF-7 breast cancer cells. Proc Natl Acad Sci USA 95, 15665-15670 (1998)
doi:10.1073/pnas.95.26.15665
66. J.S. Lee, S. Scala, Y. Matsumoto, B. Dickstein, R. Robey, Z. Zhan, G. Altenberg, and S.E. Bates: Reduced drug accumulation and multidrug resistance in human breast cancer cells without associated P-glycoprotein or MRP overexpression. J Cell Biochem 65, 513-526 (1997)
doi:10.1002/(SICI)1097-4644(19970615)65:4<513::AID-JCB7>3.0.CO;2-R
67. R.W. Robey, O. Polgar, J. Deeken, K.W. To, and S.E. Bates: ABCG2: determining its relevance in clinical drug resistance. Cancer Metastasis Rev 26, 39-57 (2007)
doi:10.1007/s10555-007-9042-6
68. M. Maliepaard, G.L. Scheffer, I.F. Faneyte, M.A. van Gastelen, A.C. Pijnenborg, A.H. Schinkel, M.J. van de Vijver, R.J. Scheper, and J.H. Schellens: Subcellular localization and distribution of the breast cancer resistance protein transporter in normal human tissues. Cancer Res 61, 3458-3464 (2001)
69. J.W. Jonker, G. Merino, S. Musters, A.E. van Herwaarden, E. Bolscher, E. Wagenaar, E. Mesman, T.C. Dale, and A.H. Schinkel: The breast cancer resistance protein BCRP (ABCG2) concentrates drugs and carcinogenic xenotoxins into milk. Nat Med 11, 127-129 (2005)
doi:10.1038/nm1186
70. A.E. van Herwaarden, E. Wagenaar, G. Merino, J.W. Jonker, H. Rosing, J.H. Beijnen, and A.H. Schinkel: Multidrug transporter ABCG2/breast cancer resistance protein secretes riboflavin (vitamin B2) into milk. Mol Cell Biol 27, 1247-1253 (2007)
doi:10.1128/MCB.01621-06
71. J.W. Jonker, J.W. Smit, R.F. Brinkhuis, M. Maliepaard, J.H. Beijnen, J.H. Schellens, and A.H. Schinkel: Role of breast cancer resistance protein in the bioavailability and fetal penetration of topotecan. J Natl Cancer Inst 92, 1651-1656 (2000)
doi:10.1093/jnci/92.20.1651
72. A.E. van Herwaarden, J.W. Jonker, E. Wagenaar, R.F. Brinkhuis, J.H. Schellens, J.H. Beijnen, and A.H. Schinkel: The breast cancer resistance protein (Bcrp1/Abcg2) restricts exposure to the dietary carcinogen 2-amino-1-methyl-6-phenylimidazo(4,5- b)pyridine. Cancer Res 63, 6447-6452 (2003)
73. S. Zhou, J.D. Schuetz, K.D. Bunting, A.M. Colapietro, J. Sampath, J.J. Morris, I. Lagutina, G.C. Grosveld, M. Osawa, H. Nakauchi, and B.P. Sorrentino: The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype. Nat Med 7, 1028-1034 (2001)
doi:10.1038/nm0901-1028
74. C.W. Scharenberg, M.A. Harkey, and B. Torok-Storb: The ABCG2 transporter is an efficient Hoechst 33342 efflux pump and is preferentially expressed by immature human hematopoietic progenitors. Blood 99, 507-512 (2002)
doi:10.1182/blood.V99.2.507
75. J.W. Jonker, M. Buitelaar, E. Wagenaar, M.A. van der Valk, G.L. Scheffer, R.J. Scheper, T. Plösch, F. Kuipers, R.P. Elferink, H. Rosing, J.H. Beijnen, and A.H. Schinkel: The breast cancer resistance protein protects against a major chlorophyll-derived dietary phototoxin and protoporphyria. Proc Natl Acad Sci USA 99, 15649-15654 (2002)
doi:10.1073/pnas.202607599
76. S. Zhou, J.J. Morris, Y. Barnes, L. Lan, J.D. Schuetz, and B.P. Sorrentino: Bcrp1 gene expression is required for normal numbers of side population stem cells in mice, and confers relative protection to mitoxantrone in hematopoietic cells in vivo. Proc Natl Acad Sci USA 99, 12339-12344 (2002)
doi:10.1073/pnas.192276999
77. T.M. Cox, G.J. Alexander, and R.P. Sarkany, R.P: Protoporphyria. Semin Liver Dis 18, 85-93 (1998)
78. J.R. Bloomer, M.J. Phillips, D.L. Davidson, and G. Klatskin: Hepatic disease in erythropoietic protoporphyria. Am J Med 58, 869-882 (1975)
doi:10.1016/0002-9343(75)90644-0
79. J.W. Jonker, S. Musters, M.L. Vlaming, T. Plösch, K.E. Gooijert, M.J. Hillebrand, H. Rosing, J.H. Beijnen, H.J. Verkade, and A.H. Schinkel: Breast cancer resistance protein (Bcrp1/Abcg2) is expressed in the harderian gland and mediates transport of conjugated protoporphyrin IX. Am J Physiol Cell Physiol 292, C2204-2212 (2007)
doi:10.1152/ajpcell.00359.2006
80. D.J. Mangelsdorf, and R.M. Evans: The RXR heterodimers and orphan receptors. Cell 83, 841-850 (1995)
doi:10.1016/0092-8674(95)90200-7
81. A.L. Bookout, Y. Jeong, M. Downes, R.T. Yu, R.M. Evans, and D.J. Mangelsdorf: Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network. Cell 126, 789-799 (2006)
doi:10.1016/j.cell.2006.06.049
82. X. Yang, M. Downes, R.T. Yu, A.L. Bookout, W. He, M. Straume, D.J. Mangelsdorf, and R.M. Evans: Nuclear receptor expression links the circadian clock to metabolism. Cell 126, 801-810 (2006)
doi:10.1016/j.cell.2006.06.050
83. J. George, and C. Liddle: Nonalcoholic Fatty liver disease: pathogenesis and potential for nuclear receptors as therapeutic targets. Mol Pharm 5, 49-59 (2008)
doi:10.1021/mp700110z
84. W., Seol, H.S. Choi, and D.D. Moore: Isolation of proteins that interact specifically with the retinoid X receptor: two novel orphan receptors. Mol Endocrinol 9, 72-85 (1995)
doi:10.1210/me.9.1.72
85. B.M. Forman, E. Goode, J. Chen, A.E. Oro, D.J. Bradley, T. Perlmann, D.J. Noonan, L.T. Burka, T. McMorris, W.W. Lamph, R.M. Evans, and C. Weinberger: Identification of a nuclear receptor that is activated by farnesol metabolites. Cell 81, 687-693 (1995)
doi:10.1016/0092-8674(95)90530-8
86. M. Makishima, A.Y. Okamoto, J.J. Repa, H. Tu, R.M. Learned, A. Luk, M.V. Hull, K.D. Lustig, D.J. Mangelsdorf, and B. Shan: Identification of a nuclear receptor for bile acids. Science 284, 1362-1365 (1999)
doi:10.1126/science.284.5418.1362
87. D.J. Parks, S.G. Blanchard, R.K. Bledsoe, G. Chandra, T.G. Consler, S.A. Kliewer, J.B. Stimmel, T.M. Willson, A.M. Zavacki, D.D. Moore, and J.M. Lehmann: Bile acids: natural ligands for an orphan nuclear receptor. Science 284, 1365-1368 (1999)
doi:10.1126/science.284.5418.1365
88. J. Yu, J.L. Lo, L. Huang, A. Zhao, E. Metzger, A. Adams, P.T. Meinke, S.D. Wright, and J. Cui: Lithocholic acid decreases expression of bile salt export pump through farnesoid X receptor antagonist activity. J Biol Chem 277, 31441-31447 (2002)
doi:10.1074/jbc.M200474200
89. P.R. Maloney, D.J. Parks, C.D. Haffner, A.M. Fivush, G. Chandra, K.D. Plunket, K.L. Creech, L.B. Moore, J.G. Wilson, M.C. Lewis, S.A. Jones, and T.M. Willson: Identification of a chemical tool for the orphan nuclear receptor FXR. J Med Chem 43, 2971-2974 (2000)
doi:10.1021/jm0002127
90. M. Downes, M.A. Verdecia, A.J. Roecker, R. Hughes, J.B. Hogenesch, H.R. Kast-Woelbern, M.E. Bowman, J.L. Ferrer, A.M. Anisfeld, P.A. Edwards, J.M. Rosenfeld, J.G. Alvarez, J.P. Noel, K.C. Nicolaou, and R.M. Evans: A chemical, genetic, and structural analysis of the nuclear bile acid receptor FXR. Mol Cell 11, 1079-1092 (2003)
doi:10.1016/S1097-2765(03)00104-7
91. M. Ananthanarayanan, N. Balasubramanian, M. Makishima, D.J. Mangelsdorf, and F.J. Suchy: Human bile salt export pump promoter is transactivated by the farnesoid X receptor/bile acid receptor. J Biol Chem 276, 28857-28865 (2001)
doi:10.1074/jbc.M011610200
92. T. Gerloff, A. Geier, I. Roots, P.J. Meier, and C. Gartung: Functional analysis of the rat bile salt export pump gene promoter. Eur J Biochem 269, 3495-3503 (2002)
doi:10.1046/j.1432-1033.2002.03030.x
93. J.R. Plass, O. Mol, J. Heegsma, M. Geuken, K.N. Faber, P.L. Jansen, and M. Müller: Farnesoid X receptor and bile salts are involved in transcriptional regulation of the gene encoding the human bile salt export pump. Hepatology 35, 589-596 (2002)
doi:10.1053/jhep.2002.31724
94. E.G. Schuetz, S. Strom, K. Yasuda, V. Lecureur, M. Assem, C. Brimer, J. Lamba, R.B. Kim, V. Ramachandran, B.J. Komoroski, R. Venkataramanan, H. Cai, C.J. Sinal, F.J. Gonzalez, and J.D. Schuetz: Disrupted bile acid homeostasis reveals an unexpected interaction among nuclear hormone receptors, transporters, and cytochrome P450. J Biol Chem 276, 39411-39418 (2001)
doi:10.1074/jbc.M106340200
95. X. Song, R. Kaimal, B. Yan, and R. Deng: Liver receptor homolog 1 transcriptionally regulates human bile salt export pump expression. J Lipid Res 49, 973-984 (2008)
doi:10.1194/jlr.M700417-JLR200
96. B. Goodwin, S.A. Jones, R.R. Price, M.A. Watson, D.D. McKee, L.B. Moore, C. Galardi, J.G. Wilson, M.C. Lewis, M.E. Roth, P.R. Maloney, T.M. Willson, and S.A. Kliewer: A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Mol Cell 6, 517-526 (2000)
doi:10.1016/S1097-2765(00)00051-4
97. T.T. Lu, M. Makishima, J.J. Repa, K. Schoonjans, T.A. Kerr, J. Auwerx, and D.J. Mangelsdorf: Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. Mol Cell 6, 507-515 (2000)
doi:10.1016/S1097-2765(00)00050-2
98. Y.K. Lee, H. Dell, D.H. Dowhan, M. Hadzopoulou-Cladaras, and D.D. Moore: The orphan nuclear receptor SHP inhibits hepatocyte nuclear factor 4 and retinoid X receptor transactivation: two mechanisms for repression. Mol Cell Biol 20, 187-195 (2000)
99. Y.K. Lee, and D.D. Moore: Dual mechanisms for repression of the monomeric orphan receptor liver receptor homologous protein-1 by the orphan small heterodimer partner. J Biol Chem 277, 2463-2467 (2002)
doi:10.1074/jbc.M105161200
100. C. Handschin, and U.A. Meyer: Regulatory network of lipid-sensing nuclear receptors: roles for CAR, PXR, LXR, and FXR. Arch Biochem Biophys 433, 387-396 (2005)
doi:10.1016/j.abb.2004.08.030
101. J.M. Lehmann, S.A. Kliewer, L.B. Moore, T.A. Smith-Oliver, B.B. Oliver, J.L. Su, S.S. Sundseth, D.A. Winegar, D.E. Blanchard, T.A. Spencer, and T.M. Willson: Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway. J Biol Chem 272, 3137-3140 (1997)
doi:10.1074/jbc.272.6.3137
102. B. Goodwin, M.A. Watson, H. Kim, J. Miao, J.K. Kemper, and S.A. Kliewer: Differential regulation of rat and human CYP7A1 by the nuclear oxysterol receptor liver X receptor-alpha. Mol Endocrinol 17, 386-394 (2003)
doi:10.1210/me.2002-0246
103. A. del Castillo-Olivares, and G. Gil: Role of FXR and FTF in bile acid-mediated suppression of cholesterol 7alphahydroxylase transcription. Nucleic Acids Res 28, 3587-3593 (2000)
doi:10.1093/nar/28.18.3587
104. A. del Castillo-Olivares, J.A. Campos, W.M. Pandak, and G. Gil: Role of FTF/LRH-1 on bile acid biosynthesis. A known nuclear receptor activator that can Act as a suppressor of bile acid biosynthesis. J Biol Chem 279, 16813-16821 (2004)
doi:10.1074/jbc.M400646200
105. D.J. Shin, J.A. Campos, G. Gil, and T.F. Osborne: PGC-1alpha activates CYP7A1 and bile acid biosynthesis. J Biol Chem 278, 50047-50052 (2003)
doi:10.1074/jbc.M309736200
106. L. Wang, Y.K. Lee, D. Bundman, Y. Han, S. Thevananther, C.S. Kim, S.S. Chua, P. Wei, R.A. Heyman, M. Karin, and D.D. Moore: Redundant pathways for negative feedback regulation of bile acid production. Dev Cell 2, 721-731 (2002)
doi:10.1016/S1534-5807(02)00187-9
107. S. Bhalla, C. Ozalp, S. Fang, L. Xiang, and J.K. Kemper: Ligand-activated pregnane X receptor interferes with HNF-4 signaling by targeting a common coactivator PGC-1alpha. Functional implications in hepatic cholesterol and glucose metabolism. J Biol Chem 279, 45139-45147 (2004)
doi:10.1074/jbc.M405423200
108. J.A. Holt, G. Luo, A.N. Billin, J. Bisi, Y.Y. McNeill, K.F. Kozarsky, M. Donahee, D.Y. Wang, T.A. Mansfield, S.A. Kliewer, B. Goodwin, and S.A. Jones: Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis. Genes Dev 17, 1581-1591 (2003)
doi:10.1101/gad.1083503
109. H. Akita, H. Suzuki, K. Ito, S. Kinoshita, N. Sato, H. and Y. Sugiyama: Characterization of bile acid transport mediated by multidrug resistance associated protein 2 and bile salt export pump. Biochim Biophys Acta 1511, 7-16 (2001)
doi:10.1016/S0005-2736(00)00355-2
110. H.R. Kast, B. Goodwin, P.T. Tarr, S.A. Jones, A.M. Anisfeld, C.M. Stoltz, P. Tontonoz, S. Kliewer, T.M. Willson, and P.A. Edwards: 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 277, 2908-2915 (2002)
doi:10.1074/jbc.M109326200
111. M. Wagner, P. Fickert, G. Zollner, A. Fuchsbichler, D. Silbert, O. Tsybrovskyy, K. Zatloukal, G.L. Guo, J.D. Schuetz, F.J. Gonzalez, H.U. Marschall, H. Denk, and M. Trauner: Role of farnesoid X receptor in determining hepatic ABC transporter expression and liver injury in bile duct-ligated mice. Gastroenterology 125, 825-838 (2003)
doi:10.1016/S0016-5085(03)01068-0
112. S. Teng, and M. Piquette-Miller: The involvement of the pregnane X receptor in hepatic gene regulation during inflammation in mice. J Pharmacol Exp Ther 312, 841-848 (2005)
doi:10.1124/jpet.104.076141
113. S. Teng, and M. Piquette-Miller: Hepatoprotective role of PXR activation and MRP3 in cholic acid-induced cholestasis. Br J Pharmacol 151, 367-376 (2007)
doi:10.1038/sj.bjp.0707235
114. G. Zollner, P. Fickert, D. Silbert, A. Fuchsbichler, H.U. Marschall, K. Zatloukal, H. Denk, and M. Trauner: Adaptive changes in hepatobiliary transporter expression in primary biliary cirrhosis. J Hepatol 38, 717-727 (2003)
doi:10.1016/S0168-8278(03)00096-5
115. L. Huang, A. Zhao, J.L. Lew, T. Zhang, Y. Hrywna, J.R. Thompson, N. de Pedro, I. Royo, R.A. Blevins, F. Peláez, S.D. Wright, and J. Cui: Farnesoid X receptor activates transcription of the phospholipid pump MDR3. J Biol Chem 278, 51085-51090 (2003)
doi:10.1074/jbc.M308321200
116. Y. Liu, J. Binz, M.J. Numerick, S. Dennis, G. Luo, B. Desai, K.I. MacKenzie, T.A. Mansfield, S.A. Kliewer, B. Goodwin, and S.A. Jones: Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra- and extrahepatic cholestasis. J Clin Invest 112, 1678-1687 (2003)
doi:10.1172/JCI200318945
117. C.J. Sinal, M. Tohkin, M. Miyata, J.M. Ward, G. Lambert, and F.J. Gonzalez: Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell 102, 731-744 (2000)
doi:10.1016/S0092-8674(00)00062-3
118. T. Kok, V.W. Bloks, H. Wolters, R. Havinga, P.L. Jansen, B. Staels, and F. Kuipers: Peroxisome proliferator-activated receptor alpha (PPARalpha)-mediated regulation of multidrug resistance 2 (Mdr2) expression and function in mice. Biochem J 369, 539-547 (2003)
doi:10.1042/BJ20020981
119. J.J. Repa, K.E. Berge, C. Pomajzl, J.A. Richardson, H. Hobbs, and D.J. Mangelsdorf: Regulation of ATP-binding cassette sterol transporters ABCG5 and ABCG8 by the liver X receptors alpha and beta. J Biol Chem 277, 18793-800 (2002)
doi:10.1074/jbc.M109927200
120. L.A. Freeman, A. Kennedy, J. Wu, S. Bark, A.T. Remaley, S. Santamarina-Fojo, and H.B. Brewer Jr: The orphan nuclear receptor LRH-1 activates the ABCG5/ABCG8 intergenic promoter. J Lipid Res 45:1197-1206 (2004)
doi:10.1194/jlr.C400002-JLR200
121. K.W. Scotto: Transcriptional regulation of ABC drug transporters. Oncogene 22, 7496-7511 (2003)
doi:10.1038/sj.onc.1206950
122. J. Sun, Z.G. He, G. Cheng, S.J. Wang, X.H. Hao, and M.J. Zhou: Multidrug resistance P-glycoprotein: crucial significance in drug disposition and interaction. Med Sci Monit 10, RA5-14 (2004)
123. T.W. Synold, I. Dussault, and B.M. Forman: The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux. Nat Med 7, 584-590 (2001)
doi:10.1038/87912
124. J.M. Maglich, C.M. Stoltz, B. Goodwin, D. Hawkins-Brown, J.T. Moore, and S.A. Kliewer: Nuclear pregnane x receptor and constitutive androstane receptor regulate overlapping but distinct sets of genes involved in xenobiotic detoxification. Mol Pharmacol 62, 638-646 (2002)
doi:10.1124/mol.62.3.638
125. G.L. Guo, G. Lambert, M. Negishi, J.M. Ward, H.B. Brewer Jr, S.A. Kliewer, F.J. Gonzalez, and C.J. Sinal: Complementary roles of farnesoid X receptor, pregnane X receptor, and constitutive androstane receptor in protection against bile acid toxicity. The small heterodimer partner interacts with the pregnane X receptor and represses its transcriptional activity. J Biol Chem 278, 45062-45071 (2003)
doi:10.1074/jbc.M307145200
126. T. Mitin, L.L. Von Moltke, M.H. Court, and D.J. Greenblatt: Levothyroxine up-regulates P-glycoprotein independent of the pregnane X receptor. Drug Metab Dispos 32, 779-782 (2004)
doi:10.1124/dmd.32.8.779
127. C. Stedman, C. Liddle, S. Coulter, J. Sonoda, J.G. Alvarez, R.M. Evans, and M. Downes: Benefit of farnesoid X receptor inhibition in obstructive cholestasis. Proc Natl Acad Sci USA 103, 11323-11328 (2006)
doi:10.1073/pnas.0604772103
128. P.L. Ee, S. Kamalakaran, D. Tonetti, X. He, D.D. Ross, and W.T. Beck: Identification of a Novel Estrogen Response Element in the Breast Cancer Resistance Protein (ABCG2) Gene. Cancer Res 64, 1247-1251 (2004)
doi:10.1158/0008-5472.CAN-03-3583
129. I. Szatmari, G. Vámosi, P. Brazda, B.L. Balint, S. Benko, L. Széles, V. Jeney, C. Ozvegy-Laczka, A. Szántó, E. Barta, J. Balla, B. Sarkadi, and L. Nagy: Peroxisome proliferator-activated receptor gamma-regulated ABCG2 expression confers cytoprotection to human dendritic cells. J Biol Chem 281, 23812-23823 (2006)
doi:10.1074/jbc.M604890200
130. S. Chitturi, and G.C. Farrell: Drug-induced cholestasis. Semin Gastrointest Dis 12, 113-124 (2001)
131. M. Trauner, and J.L. Boyer: Cholestatic syndromes. Curr Opin Gastroenterol 20, 220-230 (2004)
doi:10.1097/00001574-200405000-00006
132. A.F. Hofmann: Cholestatic liver disease: pathophysiology and therapeutic options. Liver 22, 14-19 (2002)
doi:10.1034/j.1600-0676.2002.00002.x
133. H. Higuchi, H. Miyoshi, S.F. Bronk, H. Zhang, N. Dean, and G.J. Gores: Bid antisense attenuates bile acid-induced apoptosis and cholestatic liver injury. J Pharmacol Exp Ther 299, 866-873 (2001)
134. R.E. Poupon: Ursodeoxycholic acid for primary biliary cirrhosis: lessons from the past--issues for the future. J Hepatol 32, 685-688 (2000)
doi:10.1016/S0168-8278(00)80232-9
135. C. Corpechot, F. Carrat, A. Bahr, Y. Chretien, and R.E. Poupon: The effect of ursodeoxycholic acid therapy on the natural course of primary biliary cirrhosis. Gastroenterology 128, 297-303 (2005)
doi:10.1053/j.gastro.2004.11.009
136. B.A. Mullally, and W.F. Hansen: Intrahepatic cholestasis of pregnancy: review of the literature. Obstet Gynecol Surv 57, 47-52 (2002)
doi:10.1097/00006254-200201000-00023
137. M. Leuschner, C.F. Dietrich, T. You, C. Seidl, J. Raedle, G. Herrmann, H. Ackermann, and U. Leuschner: Characterisation of patients with primary biliary cirrhosis responding to long term ursodeoxycholic acid treatment. Gut 46, 121-126 (2000)
doi:10.1136/gut.46.1.121
138. M.G. Donner, and D. Keppler: Up-regulation of basolateral multidrug resistance protein 3 (Mrp3) in cholestatic rat liver. Hepatology 34, 351-359 (2001)
doi:10.1053/jhep.2001.26213
139. G. Zollner, P. Fickert, R. Zenz, A. Fuchsbichler, C. Stumptner, L. Kenner, P. Ferenci, R.E. Stauber, G.J. Krejs, H. Denk, K. Zatloukal, and M. Trauner: Hepatobiliary transporter expression in percutaneous liver biopsies of patients with cholestatic liver diseases. Hepatology 33, 633-646 (2001)
doi:10.1053/jhep.2001.22646
140. J.L. Staudinger, B. Goodwin, S.A. Jones, D. Hawkins-Brown, K.I. MacKenzie, A. LaTour, Y. Liu, C.D. Klaassen, K.K. Brown, J. Reinhard, T.M. Willson, B.H. Koller, and S.A. Kliewer: The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity. Proc Natl Acad Sci USA 98, 3369-3374 (2001)
doi:10.1073/pnas.051551698
141. W. Xie, A. Radominska-Pandya, Y. Shi, C.M. Simon, M.C. Nelson, E.S. Ong, D.J. Waxman, and R.M. Evans: An essential role for nuclear receptors SXR/PXR in detoxification of cholestatic bile acids. Proc Natl Acad Sci USA 98, 3375-3380 (2001)
doi:10.1073/pnas.051014398
142. C.A. Stedman, C. Liddle, S.A. Coulter, J. Sonoda, J.G. Alvarez, D.D. Moore, R.M. Evans, and M. Downes: Nuclear receptors constitutive androstane receptor and pregnane X receptor ameliorate cholestatic liver injury. Proc Natl Acad Sci USA 102, 2063-2068 (2005)
doi:10.1073/pnas.0409794102
143. G. Zollner, P. Fickert, A. Fuchsbichler, D. Silbert, M. Wagner, S. Arbeiter, F.J. Gonzalez, H.U. Marschall, K. Zatloukal, H. Denk, and M. Trauner: Role of nuclear bile acid receptor, FXR, in adaptive ABC transporter regulation by cholic and ursodeoxycholic acid in mouse liver, kidney and intestine. J Hepatol 39, 480-488 (2003)
doi:10.1016/S0168-8278(03)00228-9
144. H.U. Marschall, M. Wagner, K. Bodin, G. Zollner, P. Fickert, J. Gumhold, D. Silbert, A. Fuchsbichler, J. Sjovall, and M. Trauner: Fxr(-/-) mice adapt to biliary obstruction by enhanced phase I detoxification and renal elimination of bile acids. J Lipid Res 47, 582-592 (2006).
doi:10.1194/jlr.M500427-JLR200
145. A.F. Hofmann: Primary and secondary prevention of gallstone disease: implications for patient management and research priorities. Am J Surg 165:541-548 (1993)
doi:10.1016/S0002-9610(05)80958-4
146. H. Uppal, Y. Zhai, A. Gangopadhyay, S. Khadem, S. Ren, J.A. Moser, and W. Xie: Activation of liver X receptor sensitises mice to gallbladder cholesterol crystallization. Hepatology 47, 1331-1342 (2008)
doi:10.1002/hep.22175
147. M. Downes, and C. Liddle: Look Who's Talking: Nuclear Receptors in the Liver and Gastrointestinal Tract. Cell Metab 7, 195-199 (2008)
doi:10.1016/j.cmet.2008.02.006
148. L.W. Chinn, and D.L. Kroetz: ABCB1 pharmacogenetics: progress, pitfalls, and promise. Clin Pharmacol Ther 81, 265-269 (2007)
doi:10.1038/sj.clpt.6100052
149. G. Abboud, and N. Kaplowitz: Drug-induced liver injury. Drug Saf 30, 277-294 (2007)
doi:10.2165/00002018-200730040-00001
150. S.L. Friedman: Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol Rev 88, 125-172 (2008)
doi:10.1152/physrev.00013.2007
Abbreviations: ABC: ATP-binding cassette; BDL: bile duct ligation; CA: cholic acid; CDCA: chenodeoxycholic acid; DCA:deoxycholic acid; LCA: lithocholic acid; MDR: multidrug resistance; NR: nuclear receptor; PFIC: progressive familial intrahepatic cholestasis; T-CDCA: taurochenodeoxycholic acid
Key Words: ABC Transporters, Nuclear Receptors, Hepatocyte, Liver, Bile Acids, Cholesterol, Metabolism, Review
Send correspondence to: Johan W. Jonker, The Salk Institute for Biological Studies, Howard Hughes Medical Institute and Gene Expression Laboratory, 10010 Torrey Pines Road, CA 92037, La Jolla, USA, Tel: 858-453-4100, Fax: 858-455-1349, E-mail: hjonker@salk.edu