Enterohepatic Circulation Of Bile Salts Research Articles

European Society for Paediatric Gastroenterology, Hepatology, and Nutrition Annual Meeting May 25–28, 2011 Sorrento, Italy

Objectives and Study: Ursodeoxycholate (UDCA) is used as treatment for cystic fibrosis liver disease (CFLD). It is hypothesized that the supposed therapeutic action of UDCA in CF conditions is either mediated via its choleretic activity or via effects on bile salt metabolism. In CF conditions, however, the effects of UDCA on biliary bile salt composition and on the enterohepatic circulation of bile salts have remained unclear. We evaluated, in Cftr knockout mice and wild type controls, the effects of UDCA treatment on the biliary bile salt composition and on the biosynthesis rate and pool size of cholate (CA), which is proportionally the major hydrophobic bile salt in mouse and man. Methods: Cftr-/-and control mice were either fed standard or treated with UDCA enriched chow (0.5% wt/wt) for 3 weeks. We characterized biliary bile salt composition after gallbladder cannulation and determined the CA synthesis rate and bile salt pool size using a microscale stable isotope dilution technique. Results: In non UDCA treated Cftr-/-mice the fractional biliary CA content was significantly higher compared to controls (61% vs. 46%, resp.; P

Organic anion transporter 1B1 (SLCO1B1) polymorphism and gallstone formation: High incidence of Exon4 CA genotype in female patients in North India

Gallstone disease is an important cause of abdominal morbidity Organic anion transport protein 1B1 (OATP1B1) (encoded by SLCO1B1) is a major transporter protein for bile salt uptake in enterohepatic circulation of bile salts. Disturbance in this pathway can decrease relative concentration of bile salts in gallbladder and may lead to formation of gallstones. We investigated role of SLCO1B1 polymorphisms [(Exon4 C > A (Pro155Thr; rs11045819) and Ex6 + 40T > C (Val174Ala; rs4149056)] in conferring interindividual susceptibility to gallstone disease. A total of 173 healthy controls and 226 gallstone patients (USG positive) were recruited. Genotyping was done by using standard polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method. The observed control frequencies of both polymorphisms of SLCO1B1 gene [(Exon4 C > A (Pro155Thr; rs11045819) and Ex6 + 40T > C (Val174Ala; rs4149056)] were in agreement with Hardy-Weinberg equilibrium. The frequency CA genotype and A allele of Exon4 C > A polymorphism was higher in gallstones patients (12.4% and 6.2%) as compared to controls (5.2% and 2.6%) which was statistically significant [(P = 0.029; OR = 2.31; 95% CI = 1.1-5.0); (P = 0.034; OR = 2.22; 95% CI = 1.1-4.8)], respectively). However, distribution of genotypes and alleles of Ex6 + 40T > C polymorphism was almost similar between gallstone patients and controls. Haplotype analysis showed frequency of A,T haplotype consisting of was significantly higher in gallstone patients as compared to controls and was imposing risk for the disease (P = 0.036; OR = 2.34; 95% CI = 1.0-5.1). These results suggest that SLCO1B1 Exon4 C > A polymorphism confers increased risk for gallstone disease in North Indian population.

Effects of essential fatty acid deficiency on enterohepatic circulation of bile salts in mice

Essential fatty acid (EFA) deficiency in mice has been associated with increased bile production, which is mainly determined by the enterohepatic circulation (EHC) of bile salts. To establish the mechanism underlying the increased bile production, we characterized in detail the EHC of bile salts in EFA-deficient mice using stable isotope technique, without interrupting the normal EHC. Farnesoid X receptor (FXR) has been proposed as an important regulator of bile salt synthesis and homeostasis. In Fxr(-/-) mice we additionally investigated to what extent alterations in bile production during EFA deficiency were FXR dependent. Furthermore, we tested in differentiating Caco-2 cells the effects of EFA deficiency on expression of FXR-target genes relevant for feedback regulation of bile salt synthesis. EFA deficiency-enhanced bile flow and biliary bile salt secretion were associated with elevated bile salt pool size and synthesis rate (+146 and +42%, respectively, P < 0.05), despite increased ileal bile salt reabsorption (+228%, P < 0.05). Cyp7a1 mRNA expression was unaffected in EFA-deficient mice. However, ileal mRNA expression of Fgf15 (inhibitor of bile salt synthesis) was significantly reduced, in agreement with absent inhibition of the hepatic bile salt synthesis. Bile flow and biliary secretion were enhanced to the same extent in EFA-deficient wild-type and Fxr(-/-) mice, indicating contribution of other factors besides FXR in regulation of EHC during EFA deficiency. In vitro experiments show reduced induction of mRNA expression of relevant genes upon chenodeoxycholic acid and a selective FXR agonist GW4064 stimulation in EFA-deficient Caco-2 cells. In conclusion, our data indicate that EFA deficiency is associated with interrupted negative feedback of bile salt synthesis, possibly because of reduced ileal Fgf15 expression.

T1832 Acute Biliary Pancreatitis Is Associated with Enhanced Enterohepatic Circulation of Bile Salts in a Rat Model

T1832 Acute Biliary Pancreatitis Is Associated with Enhanced Enterohepatic Circulation of Bile Salts in a Rat Model

M1728 The Enterohepatic Circulation of Bile Salts in Mice In Vivo: Effects of Essential Fatty Acid (EFA) Deficiency

M1728 The Enterohepatic Circulation of Bile Salts in Mice In Vivo: Effects of Essential Fatty Acid (EFA) Deficiency

Prebiotic oligosaccharides and the enterohepatic circulation of bile salts in rats

Human milk contains prebiotic oligosaccharides, which stimulate the growth of intestinal bifidobacteria and lactobacilli. It is unclear whether the prebiotic capacity of human milk contributes to the larger bile salt pool size and the more efficient fat absorption in infants fed human milk compared with formula. We determined the effect of prebiotic oligosaccharides on bile salt metabolism in rats. Rats were fed a control diet or an isocaloric diet containing a mixture of galactooligosaccharides (GOS), long-chain fructooligosaccharides (lcFOS), and acidified oligosaccharides (AOS) for 3 wk. We determined synthesis rate, pool size, and fractional turnover rate (FTR) of the primary bile salt cholate by using stable isotope dilution methodology. We quantified bile flow and biliary bile salt secretion rates through bile cannulation. Prebiotic intervention resulted in significant changes in fecal and colonic flora: the proportion of lactobacilli increased 344% (P < 0.01) in colon content and 139% (P < 0.01) in feces compared with the control group. The number of bifidobacteria also increased 366% (P < 0.01) in colon content and 282% in feces after the prebiotic treatment. Furthermore, pH in both colon and feces decreased significantly with 1.0 and 0.5 pH point, respectively. However, despite this alteration of intestinal bacterial flora, no significant effect on relevant parameters of bile salt metabolism and cholate kinetics was found. The present data in rats do not support the hypothesis that prebiotics naturally present in human milk contribute to a larger bile salt pool size or altered bile salt pool kinetics.

Membrane Trafficking of the Human Organic Anion-Transporting Polypeptide C (hOATPC)

The human organic anion transporting polypeptide C (OATPC) is one of the major transport proteins involved in the enterohepatic circulation of bile salts and plays an important role in vectorial transport of organic anions and drugs across hepatocytes. In this study, the effects of biological reagents on the membrane localization of OATPC were investigated by confocal microscopy and estrone-3-sulfate transport. Our results demonstrated that the functional membrane expression of fluorescent chimera OATPC-GFP was achieved in non-polarized (COS7 and HEK293) and polarized (MDCK) cells. Both brefeldin A (a Golgi complex disruptor) and bafilomycin A1 (an inhibitor of vacuolar H+-ATPase) treatment significantly decreased the polarized membrane trafficking and markedly reduced the uptake of estrone-3-sulfate ( approximately 40-90%) in OATPC-GFP transfected cells, suggesting that membrane sorting of hOATPC-GFP was mediated by Golgi complex and vacuolar H+-ATPase-related vesicle transport pathways. Treatment with 8-Br-cAMP (a cAMP analog) stimulated OATPC-GFP membrane localization and enhanced estrone-3-sulfate uptake by approximately 20%. The protein kinase A (PKA) inhibitors (H89 and KT5720), but not a PKG inhibitor, blocked the polarized membrane expression of OATPC-GFP and reduced estrone-3-sulfate transport activity. The simultaneous treatment of cells with PKA activator/inhibitor and bafilomycin A1 demonstrated that bafilomycin A1 did not change the effects of 8-Br-cAMP and H89 on the membrane localization of OATPC-GFP compared with the use of 8-Br-cAMP and H89 alone. These data suggest that a cAMP-PKA sensitive membrane sorting pathway for OATPC-GFP is independent of the vacuolar H+-ATPase associated (bafilomycin A1 sensitive) vesicle mediated membrane sorting pathway. In contrast, with combined treatment with brefeldin A, neither the PKA-activator (8-Br-cAMP) nor the inhibitor (H89) further altered the plasma membrane expression and transport activity of OATPC-GFP compared with brefeldin A treatment alone. These data suggest that the cAMP-PKA regulation of OATPC membrane expression involves the Golgi complex. When the Golgi apparatus was disrupted by brefeldin A treatment, the effects of cAMP-PKA on the Golgi-to-basolateral surface sorting process of OATPC was also diminished. In summary, the plasma membrane localization of human OATPC is mediated by Golgi complex and vacuolar H+-ATPase vesicle mediated membrane sorting pathways. cAMP-PKA regulates sorting process through the Golgi complex but not the vacuolar H+-ATPase associated vesicular pathway.

Homozygous disruption of Pctp modulates atherosclerosis in apolipoprotein E-deficient mice

Phosphatidylcholine transfer protein (PC-TP) is a cytosolic phospholipid binding protein and a member of the steroidogenic acute regulatory-related transfer domain superfamily. Its tissue distribution includes liver and macrophages. PC-TP regulates hepatic lipid metabolism, and its absence in cholesterol-loaded macrophages is associated with reduced ATP binding cassette transporter A1-mediated lipid efflux and increased susceptibility to apoptosis induced by unesterified cholesterol. To explore a role for PC-TP in atherosclerosis, we prepared PC-TP-deficient/apolipoprotein E-deficient (Pctp(-/-)/Apoe(-/-)) mice and littermate Apoe(-/-) controls. At 16 weeks, atherosclerosis was increased in chow-fed male, but not female, Pctp(-/-)/Apoe(-/-) mice. This effect was associated with increases in plasma lipid concentrations. By contrast, no differences in atherosclerosis were observed between male or female Pctp(-/-)/Apoe(-/-) mice and Apoe(-/-) controls fed a Western-type diet for 16 weeks. At 24 weeks, atherosclerosis in chow-fed male Pctp(-/-)/Apoe(-/-) mice tended to be reduced in proportion to plasma cholesterol. The attenuation of atherosclerosis in female Pctp(-/-)/Apoe(-/-) mice fed chow or the Western-type diet for 24 weeks was not attributable to changes in plasma cholesterol or triglyceride concentrations. These findings suggest that PC-TP modulates the development of atherosclerosis, in part by regulating plasma lipid concentrations.

Apical sodium bile acid transporter and ileal lipid binding protein in gallstone carriers

Although a cholesterol supersaturation of gallbladder bile has been identified as the underlying pathophysiologic defect, the molecular pathomechanism of gallstone formation in humans remains poorly understood. A deficiency of the apical sodium bile acid transporter (ASBT) and ileal lipid binding protein (ILBP) in the small intestine may result in bile acid loss into the colon and might promote gallstone formation by reducing the bile acid pool and increasing the amount of hydrophobic bile salts. To test this hypothesis, protein levels and mRNA expression of ASBT and ILBP were assessed in ileal mucosa biopsies of female gallstone carriers and controls. Neither ASBT nor ILBP levels differed significantly between gallstone carriers and controls. However, when study participants were subgrouped by body weight, ASBT and ILBP protein were 48% and 67% lower in normal weight gallstone carriers than in controls (P < 0.05); similar differences were found for mRNA expression levels. The loss of bile transporters in female normal weight gallstone carriers was coupled with a reduction of protein levels of hepatic nuclear factor 1alpha and farnesoid X receptor. In conclusion, in normal weight female gallstone carriers, the decreased expression of ileal bile acid transporters may form a molecular basis for gallstone formation.

Determinants of Cooperativity and Site Selectivity in Human Ileal Bile Acid Binding Protein

Human ileal bile acid binding protein (I-BABP) is a member of the family of intracellular lipid-binding proteins and is thought to play a role in the enterohepatic circulation of bile salts. Our group has previously shown that human I-BABP binds two molecules of glycocholate (GCA) with low intrinsic affinity but an extraordinary high degree of positive cooperativity. Besides the strong positive cooperativity, human I-BABP exhibits a high degree of site selectivity in its interactions with GCA and glycochenodeoxycholate (GCDA), the two major bile salts in humans. In this study, on the basis of our first generation nuclear magnetic resonance (NMR) structure of the ternary complex of human I-BABP with GCA and GCDA, we introduced single-residue mutations at certain key positions in the binding pocket that might disrupt a hydrogen-bonding network, a likely way of energetic communication between the two sites. Macroscopic binding parameters were determined using isothermal titration calorimetry, and site selectivity was monitored by NMR spectroscopy of isotopically enriched bile salts. According to our results, cooperativity and site selectivity are not linked in human I-BABP. While cooperativity is governed by a subtle interplay of entropic and enthalpic contributions, site selectivity appears to be determined by more localized enthalpic effects. Possible communication pathways between the two binding sites are discussed.

Topology scanning and putative three-dimensional structure of the extracellular binding domains of the apical sodium-dependent bile acid transporter (SLC10A2).

The apical sodium-dependent bile acid transporter (ASBT, SLC10A2) facilitates the enterohepatic circulation of bile salts and plays a key role in cholesterol metabolism. The membrane topology of ASBT was initially scanned using a consensus topography analysis that predominantly predicts a seven transmembrane (TM) domain configuration adhering to the "positive inside" rule. Membrane topology was further evaluated and confirmed by N-glycosylation-scanning mutagenesis, as reporter sites inserted in the putative extracellular loops 1 and 3 were glycosylated. On the basis of a 7TM topology, we built a three-dimensional model of ASBT using an approach of homology-modeling and remote-threading techniques for the extramembranous domains using bacteriorhodopsin as a scaffold for membrane attachment points; the model was refined using energy minimizations and molecular dynamics simulations. Ramachandran scores and other geometric indicators show that the model is comparable in quality to the crystal structures of similar proteins. Simulated annealing and docking of cholic acid, a natural substrate, onto the protein surface revealed four distinct binding sites. Subsequent site-directed mutagenesis of the predicted binding domain further validated the model. This model agrees further with available data for a pathological mutation (P290S) because the mutant model after in silico mutagenesis loses the ability to bind bile acids.

O0071 GENETIC VARIABILITY OF MULTI-DRUG RESISTANCE PROTEIN 3: POSSIBLE IMPACT ON FUNCTION

Introduction: Multi-drug Resistance Protein 3 (MRP3) is important in the intestinal absorption of many agents including anti-neoplastic, anti-biotic, anti-retroviral, and cardiac drugs. It also is an important mediator of the enterohepatic circulation of bile salts. Inter-individual variability in these processes is suggestive of genetic differences, but such variability is not well understood. Methods: Single Nucleotide Polymorphism (SNP) analysis of MRP3 is being performed using 24 samples from the Coriell DNA Polymorphism Discovery Resource(1), which was established to discover common variants in human DNA. Targeted genomic regions are being amplified by the polymerase chain reaction followed by high throughput sequencing using Sanger methodology. Validation of identified SNP’s is being performed on 600 DNA samples representing three distinct ethnic groups. Functional impact on absorption will be studied using MDCKII cell stable transfectants of genetic variants and measuring methotrexate transport. This study has been deemed exempt from review by the Institutional Review Board. Results: At the time of submission, 2 SNP’s have been identified. A g.+41428AT SNP was identified in 3/48 alleles and introduces a premature stop codon resulting in a truncated protein that is missing 476 amino acids (AA) relative to the wild type (1527 AA). A second SNP, g.+41112TA, is a missense variant, resulting in a S to T substitution at position 1009. The g.+41428AT variant will likely have a significant impact on transporter activity as it appears to be relatively common and results in the loss of two transmembrane (TM)- spanning helices and a nucleotide binding fold. The significance of the g.+41112TA variant is unclear at present. Although it is located in a TM, it has minimal impact on predicted protein structure or hydrophilicity. Discovery of additional variants is expected with further analysis which will be followed by an assessment of their prevalence and functional impact on MTX transport. Conclusion: Two common MRP3 polymorphisms have been discovered. Although one of the variants is predicted to have a significant impact on function, additional study is needed to define the relevance of both variants on drug absorption and enterohepatic circulation of bile salts.

Enterohepatic bile salt transporters in normal physiology and liver disease

The vectorial transport of bile salts from blood into bile is essential for the generation of bile flow, solubilization of cholesterol in bile, and emulsification of lipids in the intestine. Major transport proteins involved in the enterohepatic circulation of bile salts include the hepatocellular bile salt export pump (BSEP, ABCB11), the apical sodium-dependent bile salt transporter (ASBT, SLC10A2) in cholangiocytes and enterocytes, the sodium-dependent hepatocyte bile salt uptake system NTCP (SLC10A1), the organic anion transporting polypeptides OATP-C (SLC21A6), OATP8 (SLC21A8) and OATP-A (SLC21A3), and the multidrug resistance protein MRP3 (ABCC3). Synthesis and transport of bile salts are intricately linked processes that undergo extensive feedback and feed-forward regulation by transcriptional and posttranscriptional mechanisms. A key regulator of hepatocellular bile salt homeostasis is the bile acid receptor/farnesoid X receptor FXR, which activates transcription of the BSEP and OATP8 genes and of the small heterodimer partner 1 (SHP). SHP is a transcriptional repressor that mediates bile acid-induced repression of the bile salt uptake systems rat Ntcp and human OATP-C. A nuclear receptor that activates rodent Oatp2 (Slc21a5) and human MRP2 (ABCC2) is the pregnane X receptor/steroid X receptor PXR/SXR. Intracellular trafficking and membrane insertion of bile salt transporters is regulated by lipid, protein, and extracellular signal-related kinases in response to physiologic stimuli such as cyclic adenosine monophosphate or taurocholate. Finally, dysfunction of individual bile salt transporters such as BSEP, on account of genetic mutations, steric inhibition, suppression of gene expression, or disturbed signaling, is an important cause of cholestatic liver disease.

The enterohepatic nuclear receptors are major regulators of the enterohepatic circulation of bile salts

Recent studies have established that bile salts are signaling molecules, besides their classic function in dietary lipid absorption and cholesterol metabolism. Bile salts signal by activating mitogen-activated protein kinase (MAPK) pathways and nuclear receptors like farnesoid X receptor-α (FXRα). FXRα activation increases the expression of direct FXRα target genes involved in bile salt transport and detoxification, and decreases expression of indirect FXRα target genes involved in bile salt biosynthesis and uptake. These actions prevent toxic accumulation of bile salts in the enterohepatic organs. A network of interactions with other nuclear receptors and MAPK pathways may protect the liver against pathological elevation of bile salts and cholestasis. Therefore treatment of cholestasis might benefit from the development of FXRα agonists.

Steroid ring hydroxylation patterns govern cooperativity in human bile acid binding protein.

Human ileal bile acid binding protein (I-BABP) is a member of the intracellular lipid binding protein family. This protein is thought to function in the transcellular transport and enterohepatic circulation of bile salts. Human I-BABP binds two molecules of glycocholate, the physiologically most abundant bile salt, with modest intrinsic affinity but a remarkably high degree of positive cooperativity. Here we report a calorimetric analysis for the binding of a broad panel of bile salts to human I-BABP. The interaction of I-BABP with nine physiologically relevant derivatives of cholic acid, chenodeoxycholic acid, and deoxycholic acid in their conjugated (glycine and taurine) and unconjugated forms was monitored by isothermal titration calorimetry. All bile salts bound to I-BABP with a 2:1 stoichiometry and similar overall affinity, but the derivatives of cholic acid displayed much higher Hill coefficients, a measure of macroscopic positive cooperativity. To test whether the cooperativity was dependent on individual structural features of the bile salt side chain, a series of side-chain-extended bile salts that lacked a hydrogen bond donor or acceptor at C-24 were chemically synthesized. These synthetic variants exhibited the same energetic and cooperativity profile as the naturally occurring bile salts. Our findings indicate that cooperativity in bile salt-I-BABP recognition is governed by the pattern of steroid B- and C-ring hydroxylation and not the presence or type of side-chain conjugation.

The sodium bile salt cotransport family SLC10.

The SLC10 family of sodium/bile salt cotransporters contains over 50 members in animal, plant and bacterial species. In man, two well-characterized members and three orphan transporters are known. The Na(+)/taurocholate cotransporting polypeptide (NTCP; SLC10A1) and the apical sodium-dependent bile salt transporter (ASBT; SLC10A2) are critical components of the enterohepatic circulation of bile salts. NTCP and ASBT are cotransporters that mediate sodium-dependent, electrogenic uptake of mainly bile salts into hepatocytes (NTCP), biliary epithelial cells, ileal enterocytes and renal proximal tubular cells (ASBT).

Fat absorption and enterohepatic circulation of bile salts in cystic fibrosis mice

Fat absorption and enterohepatic circulation of bile salts in cystic fibrosis mice

The coming of age of our understanding of the enterohepatic circulation of bile salts

Recent advances in molecular biology have greatly accelerated knowledge relating to the significance of the enterohepatic circulation of bile salts. This review highlights the role that both oxysterols and bile salts play as ligands which, when bound to nuclear hormone receptors, activate transcription factors that set into play feed-forward catabolism of cholesterol to bile salts and feedback control of bile acid synthesis. The nuclear hormone receptors, liver X receptor (LXR) and farnesoid X receptor (FXR) both combined as heterodimers with retinoid X receptor and with oxysterols and bile salts, respectively as their ligands, initiate powerful genetic controls over cholesterol and bile acid homeostatic mechanisms. LXR/RXR signals molecular control of feed-forward catabolism of cholesterol to bile acids while FXR/RXR initiates feedback control of bile acid synthesis. An additional nuclear hormone receptor, small heterodimer partner (SHP), is required to inhibit the competence factor, liver receptor homolog-1 to achieve repression of bile acid synthesis in the liver and in so doing SHP autoregulates its own function. Additionally, while bile acid synthesis is repressed, pool size is preserved by the action of FXR/RXR at both hepatic and intestinal levels, which genetically signals enhanced hepatocyte bile salt transport by the bile salt export pump (BSEP) and the ileal bile acid binding protein (IBABP) for ileal reabsorption. During activation of cholesterol catabolism, LXR/RXR enhances reverse cholesterol transport by increasing cholesterol efflux via the ABC-1 transporter from extrahepatic cells. This cholesterol is then taken up by high-density lipoprotein (HDL) and transported back to the liver for further cholesterol catabolism and elimination in bile. The genetic coordination of nuclear hormone receptor function within the territory of the enterohepatic of bile salts allows for normal cholesterol and bile acid homeostasis thereby preventing atherosclerosis.

Cyclosporin a and enterohepatic circulation of bile salts in rats: decreased cholate synthesis but increased intestinal reabsorption.

Cyclosporin A (CsA) has been shown to inhibit synthesis and hepatobiliary transport of bile salts. However, effects of CsA on the enterohepatic circulation of bile salts in vivo are largely unknown. We characterized the effects of CsA on the enterohepatic circulation of cholate, with respect to synthesis rate, pool size, cycling time, intestinal absorption, and the expression of relevant transporters in liver and intestine in rats. CsA (1 mg. 100 g(-1). day(-1) s.c.) or its solvent was administered daily to male rats for 10 days. Cholate synthesis rate and pool size were determined by a 2H4-cholate dilution technique. Bile and feces were collected for determination of cholate and total bile salts, respectively. Cycling time and intestinal absorption of cholate were calculated. The mRNA levels and corresponding transporter protein levels in liver and intestine were assessed by real-time polymerase chain reaction and Western analysis, respectively. CsA treatment decreased cholate synthesis rate by 71%, but did not affect pool size or cycling time. CsA reduced the amount of cholate lost per enterohepatic cycle by approximately 70%. Protein levels of the apical sodium-dependent bile salt transporter (Asbt) were 2-fold increased in distal ileum of CsA-treated rats, due to post-transcriptional events. In conclusion, chronic CsA treatment markedly reduces cholate synthesis rate in rats, but does not affect cholate pool size or cycling time. Our results strongly suggest that CsA enhances efficacy of intestinal cholate reabsorption through increased Asbt protein expression in the distal ileum, which contributes to maintenance of cholate pool size in CsA-treated rats.

The role of the enterohepatic circulation of bile salts and nuclear hormone receptors in the regulation of cholesterol homeostasis: Bile salts as ligands for nuclear hormone receptors.

The coordinated effect of lipid activated nuclear hormone receptors; liver X receptor (LXR), bound by oxysterol ligands and farnesoid X receptor (FXR), bound by bile acid ligands, act as genetic transcription factors to cause feed-forward cholesterol catabolism to bile acids and feedback repression of bile acid synthesis, respectively. It is the coordinated action of LXR and FXR, each dimerized to retinoid X receptor, that signal nuclear DNA response elements to encode proteins that prevent excessive cholesterol accumulation and bile salt toxicity, respectively. LXR helps prevent hypercholesterolemia by enhancing transporters for cholesterol efflux that enhance reverse cholesterol transport, while FXR enhances intestinal reabsorption and preservation of bile salts by increasing the ileal bile acid binding protein. FXR also targets sodium taurocholate cotransport peptide and bile salt export pump (protein) genes to limit bile salt uptake and enhance export, respectively, which prevents bile salt toxicity. Other nuclear hormone receptors such as pregnan X receptor, which share the obligate partner, retinoid X receptor, and vitamin D receptor also function as bile acid sensors to signal detoxification by hydroxylation of toxic bile acids. Pharmacologically targeted receptor agonists (or antagonists) may be developed that alter cholesterol and bile salt concentrations by modulating nuclear hormone receptors and/or their coactivators or corepressors to positively affect cholesterol homeostasis and bile salt metabolism. It is the coordinated transcription factor action of LXR, which responds to ligand binding of circulating oxysterols in both liver and peripheral tissues, and FXR responding to bile salts within the enterohepatic circulation that make possible the regulation of cholesterol and bile acid homeostasis.