Background: Nuclear receptors (NRs) form a family of 48 members. NRs control hepatic processes such as bile acid homeostasis, lipid metabolism and mechanisms involved in fibrosis and inflammation. Due to their central role in the regulation of hepatoprotective mechanisms, NRs are promising therapeutic targets in cholestatic disorders. Key Messages: NRs can be classified into five different physiological clusters. NRs from the ‘bile acids and xenobiotic metabolism' and from the ‘lipid metabolism and energy homeostasis' clusters are strongly expressed in the liver. Furthermore, NRs from these clusters, such as farnesoid X receptor α (FXRα), pregnane X receptor (PXR) and peroxisome proliferator-activated receptors (PPARs), have been associated with the pathogenesis and the progression of cholestasis. The latter observation is also true for vitamin D receptor (VDR), which is barely detectable in the whole liver, but has been linked to cholestatic diseases. Involvement of VDR in cholestasis is ascribed to a strong expression in nonparenchymal liver cells, such as biliary epithelial cells, Kupffer cells and hepatic stellate cells. Likewise, NRs from other physiological clusters with low hepatic expression, such as estrogen receptor α (ERα) or reverse-Erb α/β (REV-ERB α/β), may also control pathophysiological processes in cholestasis. Conclusions: In this review, we will describe the impact of individual NRs on cholestasis. We will then discuss the potential role of these transcription factors as therapeutic targets.

Keywords:
Nuclear receptors, Cholestasis, Liver cells
1.
Mangelsdorf DJ, Evans RM: The RXR heterodimers and orphan receptors. Cell 1995;83:841-850.
2.
Arrese M, Karpen SJ: Nuclear receptors, inflammation, and liver disease: insights for cholestatic and fatty liver diseases. Clin Pharmacol Ther 2010;87:473-478.
3.
Chawla A, Repa JJ, Evans RM, Mangelsdorf DJ: Nuclear receptors and lipid physiology: opening the X-files. Science 2001;294:1866-1870.
4.
Gronemeyer H, Gustafsson JA, Laudet V: Principles for modulation of the nuclear receptor superfamily. Nat Rev Drug Discov 2004;3:950-964.
5.
Bookout AL, Jeong Y, Downes M, Yu RT, Evans RM, Mangelsdorf DJ: Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network. Cell 2006;126:789-799.
6.
Karpen SJ: Nuclear receptor regulation of hepatic function. J Hepatol 2002;36:832-850.
7.
Yang X, Downes M, Yu RT, Bookout AL, He W, Straume M, Mangelsdorf DJ, Evans RM: Nuclear receptor expression links the circadian clock to metabolism. Cell 2006;126:801-810.
8.
Vacca M, D'Amore S, Graziano G, D'Orazio A, Cariello M, Massafra V, Salvatore L, Martelli N, Murzilli S, Lo Sasso G, Mariani-Costantini R, Moschetta A: Clustering nuclear receptors in liver regeneration identifies candidate modulators of hepatocyte proliferation and hepatocarcinoma. PloS One 2014;9:e104449.
9.
Gascon-Barre M, Demers C, Mirshahi A, Neron S, Zalzal S, Nanci A: The normal liver harbors the vitamin D nuclear receptor in nonparenchymal and biliary epithelial cells. Hepatology 2003;37:1034-1042.
10.
Zollner G, Trauner M: Nuclear receptors as therapeutic targets in cholestatic liver diseases. Br J Pharmacol 2009;156:7-27.
11.
Wagner M, Zollner G, Trauner M: Nuclear receptors in liver disease. Hepatology 2011;53:1023-1034.
12.
Halilbasic E, Baghdasaryan A, Trauner M: Nuclear receptors as drug targets in cholestatic liver diseases. Clin Liver Dis 2013;17:161-189.
13.
Alvarez L, Jara P, Sanchez-Sabate E, Hierro L, Larrauri J, Diaz MC, Camarena C, De la Vega A, Frauca E, Lopez-Collazo E, Lapunzina P: Reduced hepatic expression of farnesoid X receptor in hereditary cholestasis associated to mutation in ATP8B1. Hum Mol Genet 2004;13:2451-2460.
14.
Demeilliers C, Jacquemin E, Barbu V, Mergey M, Paye F, Fouassier L, Chignard N, Housset C, Lomri NE: Altered hepatobiliary gene expressions in PFIC1: ATP8B1 gene defect is associated with CFTR downregulation. Hepatology 2006;43:1125-1134.
15.
Zollner G, Wagner M, Fickert P, Silbert D, Gumhold J, Zatloukal K, Denk H, Trauner M: Expression of bile acid synthesis and detoxification enzymes and the alternative bile acid efflux pump MRP4 in patients with primary biliary cirrhosis. Liver Int 2007;27:920-929.
16.
Liu Y, Binz J, Numerick MJ, Dennis S, Luo G, Desai B, MacKenzie KI, Mansfield TA, Kliewer SA, Goodwin B, Jones SA: Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra- and extrahepatic cholestasis. J Clin Invest 2003;112:1678-1687.
17.
Wagner M, Fickert P, Zollner G, Fuchsbichler A, Silbert D, Tsybrovskyy O, Zatloukal K, Guo GL, Schuetz JD, Gonzalez FJ, Marschall HU, Denk H, Trauner M: Role of farnesoid X receptor in determining hepatic ABC transporter expression and liver injury in bile duct-ligated mice. Gastroenterology 2003;125:825-838.
18.
Stedman CA, Liddle C, Coulter SA, Sonoda J, Alvarez JG, Moore DD, Evans RM, Downes M: Nuclear receptors constitutive androstane receptor and pregnane X receptor ameliorate cholestatic liver injury. Proc Natl Acad Sci USA 2005;102:2063-2068.
19.
Wang YD, Chen WD, Wang M, Yu D, Forman BM, Huang W: Farnesoid X receptor antagonizes nuclear factor kappaB in hepatic inflammatory response. Hepatology 2008;48:1632-1643.
20.
Fiorucci S, Rizzo G, Antonelli E, Renga B, Mencarelli A, Riccardi L, Orlandi S, Pruzanski M, Morelli A, Pellicciari R: A farnesoid X receptor-small heterodimer partner regulatory cascade modulates tissue metalloproteinase inhibitor-1 and matrix metalloprotease expression in hepatic stellate cells and promotes resolution of liver fibrosis. J Pharmacol Exp Ther 2005;314:584-595.
21.
Hirschfield GM, Mason AL, Gordon SC, Luketic V, Mayo M, Vincent C, Lindor KD, Pares A, Kowdley KV, Trauner M, Esguerra M, Boehm O, Shapiro DA: A long term safety extension trial of the farnesoid X receptor (FXR) agonist obeticholic acid (OCA) and UDCA in primary biliary cirrhosis (PBC). Hepatology 2011;54:429.
22.
Mason A, Luketic V, Lindor K, Hirschfield GM, Gordon SC, Mayo M, Kowdley KV, Pares A, Trauner M, Sciacca CI, jONES TB, Pruzanski M, Shapiro DA: Farnesoid-X receptor agonists: a new class of drugs for the treatment of PBC? An international study evaluating the addition of obeticholic acid (INT-747) to ursodeoxycholic acid. Hepatology 2010:357.
23.
Kowdley KV, Jones D, Luketic V: The OCA PBC Study Group. An international study evaluating the farnesoid X receptor agonist obeticholic acid in monotherapy in PBC. J Hepatol 2012;54:S13.
24.
Park YJ, Qatanani M, Chua SS, LaRey JL, Johnson SA, Watanabe M, Moore DD, Lee YK: Loss of orphan receptor small heterodimer partner sensitizes mice to liver injury from obstructive cholestasis. Hepatology 2008;47:1578-1586.
25.
Zhang Y, Xu N, Xu J, Kong B, Copple B, Guo GL, Wang L: E2F1 is a novel fibrogenic gene that regulates cholestatic liver fibrosis through the Egr-1/SHP/EID1 network. Hepatology 2014;60:919-930.
26.
Staudinger JL, Goodwin B, Jones SA, Hawkins-Brown D, MacKenzie KI, LaTour A, Liu Y, Klaassen CD, Brown KK, Reinhard J, Willson TM, Koller BH, Kliewer SA: The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity. Proc Natl Acad Sci USA 2001;98:3369-3374.
27.
Xie W, Barwick JL, Simon CM, Pierce AM, Safe S, Blumberg B, Guzelian PS, Evans RM: Reciprocal activation of xenobiotic response genes by nuclear receptors SXR/PXR and CAR. Genes Dev 2000;14:3014-3023.
28.
Wagner M, Halilbasic E, Marschall HU, Zollner G, Fickert P, Langner C, Zatloukal K, Denk H, Trauner M: CAR and PXR agonists stimulate hepatic bile acid and bilirubin detoxification and elimination pathways in mice. Hepatology 2005;42:420-430.
29.
Chen HL, Liu YJ, Chen HL, Wu SH, Ni YH, Ho MC, Lai HS, Hsu WM, Hsu HY, Tseng HC, Jeng YM, Chang MH: Expression of hepatocyte transporters and nuclear receptors in children with early and late-stage biliary atresia. Pediatr Res 2008;63:667-673.
30.
Castano G, Burgueno A, Fernandez Gianotti T, Pirola CJ, Sookoian S: The influence of common gene variants of the xenobiotic receptor (PXR) in genetic susceptibility to intrahepatic cholestasis of pregnancy. Aliment Pharmacol Ther 2010;31:583-592.
31.
Karlsen TH, Lie BA, Frey Froslie K, Thorsby E, Broome U, Schrumpf E, Boberg KM: Polymorphisms in the steroid and xenobiotic receptor gene influence survival in primary sclerosing cholangitis. Gastroenterology 2006;131:781-787.
32.
Kimura Y, Selmi C, Leung PS, Mao TK, Schauer J, Watnik M, Kuriyama S, Nishioka M, Ansari AA, Coppel RL, Invernizzi P, Podda M, Gershwin ME: Genetic polymorphisms influencing xenobiotic metabolism and transport in patients with primary biliary cirrhosis. Hepatology 2005;41:55-63.
33.
Wallace K, Cowie DE, Konstantinou DK, Hill SJ, Tjelle TE, Axon A, Koruth M, White SA, Carlsen H, Mann DA, Wright MC: The PXR is a drug target for chronic inflammatory liver disease. J Steroid Biochem Mol Biol 2010;120:137-148.
34.
Haughton EL, Tucker SJ, Marek CJ, Durward E, Leel V, Bascal Z, Monaghan T, Koruth M, Collie-Duguid E, Mann DA, Trim JE, Wright MC: Pregnane X receptor activators inhibit human hepatic stellate cell transdifferentiation in vitro. Gastroenterology 2006;131:194-209.
35.
Lakatos LP, Bajnok E, Hegedus D, Toth T, Lakatos P, Szalay F: Vitamin D receptor, oestrogen receptor-alpha gene and interleukin-1 receptor antagonist gene polymorphisms in Hungarian patients with primary biliary cirrhosis. Eur J Gastroenterol Hepatol 2002;14:733-740.
36.
Kempinska-Podhorecka A, Wunsch E, Jarowicz T, Raszeja-Wyszomirska J, Loniewska B, Kaczmarczyk M, Milkiewicz M, Milkiewicz P: Vitamin D receptor polymorphisms predispose to primary biliary cirrhosis and severity of the disease in polish population. Gastroenterol Res Pract 2012;2012:408723.
37.
Halmos B, Szalay F, Cserniczky T, Nemesanszky E, Lakatos P, Barlage S, Schmitz G, Romics L, Csaszar A: Association of primary biliary cirrhosis with vitamin D receptor BsmI genotype polymorphism in a Hungarian population. Dig Dis Sci 2000;45:1091-1095.
38.
Fan L, Tu X, Zhu Y, Zhou L, Pfeiffer T, Feltens R, Stoecker W, Zhong R: Genetic association of vitamin D receptor polymorphisms with autoimmune hepatitis and primary biliary cirrhosis in the Chinese. J Gastroenterol Hepatol 2005;20:249-255.
39.
Tanaka A, Nezu S, Uegaki S, Kikuchi K, Shibuya A, Miyakawa H, Takahashi S, Bianchi I, Zermiani P, Podda M, Ohira H, Invernizzi P, Takikawa H: Vitamin D receptor polymorphisms are associated with increased susceptibility to primary biliary cirrhosis in Japanese and Italian populations. J Hepatol 2009;50:1202-1209.
40.
D'Aldebert E, Biyeyeme Bi Mve MJ, Mergey M, Wendum D, Firrincieli D, Coilly A, Fouassier L, Corpechot C, Poupon R, Housset C, Chignard N: Bile salts control the antimicrobial peptide cathelicidin through nuclear receptors in the human biliary epithelium. Gastroenterology 2009;136:1435-1443.
41.
Firrincieli D, Zuniga S, Rey C, Wendum D, Lasnier E, Rainteau D, Braescu T, Falguieres T, Boissan M, Cadoret A, Housset C, Chignard N: Vitamin D nuclear receptor deficiency promotes cholestatic liver injury by disruption of biliary epithelial cell junctions in mice. Hepatology 2013;58:1401-1412.
42.
Hochrath K, Stokes CS, Geisel J, Pollheimer MJ, Fickert P, Dooley S, Lammert F: Vitamin D modulates biliary fibrosis in ABCB4-deficient mice. Hepatol Int 2014;8:443-452.
43.
Fickert P, Fuchsbichler A, Moustafa T, Wagner M, Zollner G, Halilbasic E, Stoger U, Arrese M, Pizarro M, Solis N, Carrasco G, Caligiuri A, Sombetzki M, Reisinger E, Tsybrovskyy O, Zatloukal K, Denk H, Jaeschke H, Pinzani M, Trauner M: Farnesoid X receptor critically determines the fibrotic response in mice but is expressed to a low extent in human hepatic stellate cells and periductal myofibroblasts. Am J Pathol 2009;175:2392-2405.
44.
Ding N, Yu RT, Subramaniam N, Sherman MH, Wilson C, Rao R, Leblanc M, Coulter S, He M, Scott C, Lau SL, Atkins AR, Barish GD, Gunton JE, Liddle C, Downes M, Evans RM: A vitamin D receptor/SMAD genomic circuit gates hepatic fibrotic response. Cell 2013;153:601-613.
45.
Yue HY, Yin C, Hou JL, Zeng X, Chen YX, Zhong W, Hu PF, Deng X, Tan YX, Zhang JP, Ning BF, Shi J, Zhang X, Wang HY, Lin Y, Xie WF: Hepatocyte nuclear factor 4alpha attenuates hepatic fibrosis in rats. Gut 2010;59:236-246.
46.
Inamine T, Higa S, Noguchi F, Kondo S, Omagari K, Yatsuhashi H, Tsukamoto K, Nakamura M: Association of genes involved in bile acid synthesis with the progression of primary biliary cirrhosis in Japanese patients. J Gastroenterol 2013;48:1160-1170.
47.
Lee YK, Schmidt DR, Cummins CL, Choi M, Peng L, Zhang Y, Goodwin B, Hammer RE, Mangelsdorf DJ, Kliewer SA: Liver receptor homolog-1 regulates bile acid homeostasis but is not essential for feedback regulation of bile acid synthesis. Mol Endocrinol 2008;22:1345-1356.
48.
Mataki C, Magnier BC, Houten SM, Annicotte JS, Argmann C, Thomas C, Overmars H, Kulik W, Metzger D, Auwerx J, Schoonjans K: Compromised intestinal lipid absorption in mice with a liver-specific deficiency of liver receptor homolog 1. Mol Cell Biol 2007;27:8330-8339.
49.
Honda A, Ikegami T, Nakamuta M, Miyazaki T, Iwamoto J, Hirayama T, Saito Y, Takikawa H, Imawari M, Matsuzaki Y: Anticholestatic effects of bezafibrate in patients with primary biliary cirrhosis treated with ursodeoxycholic acid. Hepatology 2013;57:1931-1941.
50.
Ghonem NS, Ananthanarayanan M, Soroka CJ, Boyer JL: Peroxisome proliferator-activated receptor α activates human multidrug resistance transporter 3/ATP-binding cassette protein subfamily B4 transcription and increases rat biliary phosphatidylcholine secretion. Hepatology 2014;59:1030-1042.
51.
Lee J, Hong EM, Byun HW, Choi MH, Jang HJ, Eun CS, Kae SH, Choi HS: The effect of PPARalpha and PPARgamma ligands on inflammation and ABCA1 expression in cultured gallbladder epithelial cells. Dig Dis Sci 2008;53:1707-1715.
52.
Moustafa T, Fickert P, Magnes C, Guelly C, Thueringer A, Frank S, Kratky D, Sattler W, Reicher H, Sinner F, Gumhold J, Silbert D, Fauler G, Hofler G, Lass A, Zechner R, Trauner M: Alterations in lipid metabolism mediate inflammation, fibrosis, and proliferation in a mouse model of chronic cholestatic liver injury. Gastroenterology 2012;142:140-151 e112.
53.
Xia X, Jung D, Webb P, Zhang A, Zhang B, Li L, Ayers SD, Gabbi C, Ueno Y, Gustafsson JA, Alpini G, Moore DD, Lesage GD: Liver X receptor beta and peroxisome proliferator-activated receptor delta regulate cholesterol transport in murine cholangiocytes. Hepatology 2012;56:2288-2296.
54.
Iwaisako K, Haimerl M, Paik YH, Taura K, Kodama Y, Sirlin C, Yu E, Yu RT, Downes M, Evans RM, Brenner DA, Schnabl B: Protection from liver fibrosis by a peroxisome proliferator-activated receptor delta agonist. Proc Natl Acad Sci USA 2012;109:E1369-E1376.
55.
Harada K, Isse K, Kamihira T, Shimoda S, Nakanuma Y: Th1 cytokine-induced downregulation of PPARgamma in human biliary cells relates to cholangitis in primary biliary cirrhosis. Hepatology 2005;41:1329-1338.
56.
Lv X, Song JG, Li HH, Ao JP, Zhang P, Li YS, Song SL, Wang XR: Decreased hepatic peroxisome proliferator-activated receptor-gamma contributes to increased sensitivity to endotoxin in obstructive jaundice. World J Gastroenterol 2011;17:5267-5273.
57.
Baghdasaryan A, Claudel T, Kosters A, Gumhold J, Silbert D, Thuringer A, Leski K, Fickert P, Karpen SJ, Trauner M: Curcumin improves sclerosing cholangitis in Mdr2-/- mice by inhibition of cholangiocyte inflammatory response and portal myofibroblast proliferation. Gut 2010;59:521-530.
58.
Marra F, DeFranco R, Robino G, Novo E, Efsen E, Pastacaldi S, Zamara E, Vercelli A, Lottini B, Spirli C, Strazzabosco M, Pinzani M, Parola M: Thiazolidinedione treatment inhibits bile duct proliferation and fibrosis in a rat model of chronic cholestasis. World J Gastroenterol 2005;11:4931-4938.
59.
Zandieh Doulabi B, Platvoet-ter Schiphorst M, van Beeren HC, Labruyere WT, Lamers WH, Fliers E, Bakker O, Wiersinga WM: Tr(beta)1 protein is preferentially expressed in the pericentral zone of rat liver and exhibits marked diurnal variation. Endocrinology 2002;143:979-984.
60.
Fava G, Ueno Y, Glaser S, Francis H, Demorrow S, Marucci L, Marzioni M, Benedetti A, Venter J, Vaculin B, Vaculin S, Alpini G: Thyroid hormone inhibits biliary growth in bile duct-ligated rats by PLC/IP(3)/Ca(2+)-dependent downregulation of SRC/ERK1/2. Am J Physiol Cell Physiol 2007;292:C1467-C1475.
61.
Pascussi JM, Gerbal-Chaloin S, Drocourt L, Maurel P, Vilarem MJ: The expression of CYP2B6, CYP2C9 and CYP3A4 genes: a tangle of networks of nuclear and steroid receptors. Biochim Biophys Acta 2003;1619:243-253.
62.
Pascussi JM, Gerbal-Chaloin S, Fabre JM, Maurel P, Vilarem MJ: Dexamethasone enhances constitutive androstane receptor expression in human hepatocytes: consequences on cytochrome P450 gene regulation. Mol Pharmacol 2000;58:1441-1450.
63.
Rautiainen H, Karkkainen P, Karvonen AL, Nurmi H, Pikkarainen P, Nuutinen H, Farkkila M: Budesonide combined with UDCA to improve liver histology in primary biliary cirrhosis: a three-year randomized trial. Hepatology 2005;41:747-752.
64.
Arenas F, Hervias I, Uriz M, Joplin R, Prieto J, Medina JF: Combination of ursodeoxycholic acid and glucocorticoids upregulates the AE2 alternate promoter in human liver cells. J Clin Invest 2008;118:695-709.
65.
Yamanishi Y, Nosaka Y, Kawasaki H, Hirayama C, Ikawa S: Sterol and bile acid metabolism after short-term prednisolone treatment in patients with chronic active hepatitis. Gastroenterol Jpn 1985;20:246-251.
66.
Lu Y, Zhang Z, Xiong X, Wang X, Li J, Shi G, Yang J, Zhang X, Zhang H, Hong J, Xia X, Ning G, Li X: Glucocorticoids promote hepatic cholestasis in mice by inhibiting the transcriptional activity of the farnesoid X receptor. Gastroenterology 2012;143:1630-1640 e1638.
67.
Uppal H, Saini SP, Moschetta A, Mu Y, Zhou J, Gong H, Zhai Y, Ren S, Michalopoulos GK, Mangelsdorf DJ, Xie W: Activation of LXRs prevents bile acid toxicity and cholestasis in female mice. Hepatology 2007;45:422-432.
68.
Wang YY, Dahle MK, Agren J, Myhre AE, Reinholt FP, Foster SJ, Collins JL, Thiemermann C, Aasen AO, Wang JE: Activation of the liver X receptor protects against hepatic injury in endotoxemia by suppressing Kupffer cell activation. Shock 2006;25:141-146.
69.
Harada K, Yuko K, Sato Y, Ikeda H, Nakanuma Y: Significance of oestrogen-related receptor gamma on biliary epithelial cells in the pathogenesis of primary biliary cirrhosis. J Clin Pathol 2014;67:566-572.
70.
Noshiro M, Usui E, Kawamoto T, Kubo H, Fujimoto K, Furukawa M, Honma S, Makishima M, Honma K, Kato Y: Multiple mechanisms regulate circadian expression of the gene for cholesterol 7alpha-hydroxylase (Cyp7a), a key enzyme in hepatic bile acid biosynthesis. J Biol Rhythms 2007;22:299-311.
71.
Duez H, van der Veen JN, Duhem C, Pourcet B, Touvier T, Fontaine C, Derudas B, Bauge E, Havinga R, Bloks VW, Wolters H, van der Sluijs FH, Vennstrom B, Kuipers F, Staels B: Regulation of bile acid synthesis by the nuclear receptor Rev-erbalpha. Gastroenterology 2008;135:689-698.
72.
Li T, Eheim AL, Klein S, Uschner FE, Smith AC, Brandon-Warner E, Ghosh S, Bonkovsky HL, Trebicka J, Schrum LW: Novel role of nuclear receptor Rev-erbalpha in hepatic stellate cell activation: potential therapeutic target for liver injury. Hepatology 2014;59:2383-2396.
73.
Alvaro D, Invernizzi P, Onori P, Franchitto A, De Santis A, Crosignani A, Sferra R, Ginanni-Corradini S, Mancino MG, Maggioni M, Attili AF, Podda M, Gaudio E: Estrogen receptors in cholangiocytes and the progression of primary biliary cirrhosis. J Hepatol 2004;41:905-912.
74.
Alvaro D, Mancino MG, Onori P, Franchitto A, Alpini G, Francis H, Glaser S, Gaudio E: Estrogens and the pathophysiology of the biliary tree. World J Gastroenterol 2006;12:3537-3545.
75.
Milona A, Owen BM, Cobbold JF, Willemsen EC, Cox IJ, Boudjelal M, Cairns W, Schoonjans K, Taylor-Robinson SD, Klomp LW, Parker MG, White R, van Mil SW, Williamson C: Raised hepatic bile acid concentrations during pregnancy in mice are associated with reduced farnesoid X receptor function. Hepatology 2010;52:1341-1349.
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